5-aminopyrazole-4-carboxamide inhibitors of cdpk1 from t. gondii and c. parvum

ABSTRACT

The present disclosure is generally directed to compositions and methods for treating apicomplexan protozoan related disease, such as toxoplasmosis and cryptosporidiosis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the filing dates of U.S.Provisional Patent Application Ser. No. 61/825,364, filed May 20, 2013,and U.S. Provisional Patent Application Ser. No. 61/889,451, filed Oct.10, 2013, each of which are hereby incorporated by reference in theirentirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under Grant No.R01AI089441, awarded by the National Institutes of Health (NIH). Thegovernment has certain rights in the invention.

BACKGROUND OF THE INVENTION

Field of the Invention

The present disclosure is generally directed to compositions and methodsfor treating apicomplexan protozoan related disease, such astoxoplasmosis and cryptosporidiosis.

Description of Related Art

Toxoplasma gondii (T. gondii) and Cryptosporidium parvum (C. parvum) areapicomplexan parasites that cause serious diseases in humans(toxoplasmosis and cryptosporidiosis) with inadequate treatment options.C. parvum infection has been implicated in 15-20% of childhood diarrheacases in developing countries and can lead to life-threatening illnessin immunocompromised persons. The only approved medicine for C. parvuminfection, nitazoxanide, is expensive and not very effective fortreating immunocompromised patients. Toxoplasmosis also leads tolife-threatening situations in immunocompromised patients. T. gondiiinfection of pregnant women can result in severe birth defects ormiscarriage.

The calcium-dependent protein kinase-1 orthologs of both T. gondii(TgCDPK1) and C. parvum (CpCDPK1) have attracted interest as potentialdrug targets for these parasites. CDPK1 belongs to a family ofserine/threonine protein kinases found in plants and Apicomplexa but notin humans or other animals. Recent genetic and chemical evidencesuggests that TgCDPK1 plays critical role in the lifecycle of T. gondiiparasites by controlling the exocytosis of micronemes, which arespecialized organelles that contain a number of proteins involved inparasite invasion and egress. CpCDPK1 is likely of importance to thelifecycle of C. parvum for similar reasons.

SUMMARY OF THE INVENTION

Current options for treatment of C. parvum and T gondii infections arelimited to sulfadiazine and pyrimethamine, which can have toxic sideeffects and require lifelong treatment for immunocompromised persons.The present disclosure provides new and effective compounds for treatingapicomplexan-related disorders, including those caused by the infectiouseukaryotic parasite T. gondii, C. parvum and Cryptosporidium hominus (C.hominus), with no toxic side effects, such as cardiotoxicity. Inaddition, the compounds of the disclosure provide good oralbioavailability and compound stability in vivo.

Thus, one aspect of the disclosure provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof, whereinR¹ is one of the formulas:

wherein

-   -   n is 0, 1, or 2;    -   each R⁷ (at any available position on the ring) is independently        halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR¹⁰, —SR¹⁰,        —N(R¹⁰)₂, —C(O)R¹⁰, —C(O)OR¹⁰ —C(O)N(R¹⁰)₂, —S(O)₂R¹⁰        —OC(O)OR¹⁰, —OC(O)N(R¹⁰)₂, —N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)C(O)OR¹⁰, or        —N(R¹⁰)C(O)N(R¹⁰)₂, wherein each R¹⁰ is independently hydrogen        or C₁₋₆ alkyl;    -   R⁸ is hydrogen, halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆        haloalkyl, or —Q—R⁸;    -   Q is —O—, —S—, —NH—, or —N(C₁₋₆ alkyl)—;    -   R⁸ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₈        cycloalkyl, heterocyclyl, aryl, aryl C₁₋₆ alkyl, heteroaryl, or        heteroaryl C₁₋₆ alkyl, wherein the alkyl, aryl, arylalkyl,        heteroaryl, and heteroarylalkyl are optionally substituted with        one, two, three, or four groups that are each independently        halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR¹⁴, —SR¹⁴,        —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —S(O)₂R¹⁴,        —OC(O)R¹⁴, —OC(O)OR¹⁴, —OC(O)N(R¹⁴)₂, —N(R¹⁴)C(O)R¹⁴,        —N(R¹⁴)C(O)OR¹⁴, or —N(R¹⁴)C(O)N(R¹⁴)₂, wherein each R¹⁴ is        independently hydrogen or C₁₋₆ alkyl; and    -   each R⁹ is independently hydrogen or C₁₋₆ alkyl;

-   R² is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —C₁₋₄ alkyl-R¹², C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, monocyclic heterocyclyl,    monocyclic heteroaryl, or phenyl, wherein the alkyl, cycloalkyl,    heterocyclyl, heteroaryl, and phenyl groups are each optionally    substituted with one or two R¹³ groups;    -   each R¹³ is independently C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR, —SR,        —NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —S(O)₂NR₂, or —S(O)₂R; and    -   where R¹² is —OR, —SR, —NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —S(O)₂R,        —OC(O)R, —OC(O)OR, —OC(O)NR₂, —N(R)C(O)R, —N(R)C(O)OR,        —N(R)C(O)NR₂, phenyl, monocyclic heteroaryl, C₃₋₈ cycloalkyl, or        monocyclic heterocyclyl, wherein the aryl, heteroaryl, C₃₋₈        cycloalkyl, and heterocyclyl groups are each optionally        substituted by one, two, or three groups that are each        independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl,        —OR, —SR, —NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —S(O)₂R, —OC(O)R,        —OC(O)OR, —OC(O)NR₂, —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)NR₂;        -   and each R is independently hydrogen, C₁₋₆ alkyl, C₂₋₆            alkenyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, heterocyclyl,            aryl, aryl C₁₋₆ alkyl, heteroaryl, or heteroaryl C₁₋₆ alkyl,            wherein the alkyl, aryl, arylalkyl, heteroaryl, and            heteroarylalkyl are optionally substituted with one, two,            three, or four groups that are each independently halogen,            cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁰, —SR⁰,            —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R)₂, —S(O)₂R⁰, —OC(O)R⁰,            —OC(O)OR⁰, —OC(O)N(R⁰)₂, —N(R⁰)C(O)R⁰, —N(R⁰)C(O)OR⁰, or            —N(R⁰)C(O)N(R⁰)₂, wherein each R⁰ is independently hydrogen            or C₁₋₆ alkyl;        -   or R² and R³ together with the atoms to which they are            attached form a heterocyclyl optionally substituted with one            or two R¹³ groups;

-   R³ and R⁴ are independently selected from hydrogen and C₁₋₆ alkyl;    and

-   R⁵ and R⁶ are independently selected from hydrogen and C₁₋₆ alkyl.

In another aspect, the disclosure provides pharmaceutical compositionscomprising one or more of compounds of the disclosure and apharmaceutically acceptable carrier, diluent, or excipient.

In another aspect, the disclosure provides methods for treating anapicomplexan protozoan related disease comprising providing to a patientin need of such treatment a therapeutically effective amount of either(i) one or more of compounds of the disclosure or (ii) a pharmaceuticalcomposition comprising one or more of compounds of the disclosure and apharmaceutically acceptable excipient, carrier, or diluent. In otheraspect, the apicomplexan protozoan related disease is toxoplasmosis,cryptosporidiosis, malaria neosporosis, eimeriosis, or coccidiosis.

In another aspect, the compounds of the disclosure inhibit apicomplexancalcium dependent protein kinases, including but not limited to T.gondii calcium dependent protein kinases (TgCDPKs) or C. parvum and C.hominus calcium dependent protein kinases (CpCDPKs).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a close-up view of inhibitors in an overlay ofTgCDPK1-bound 35 (2.0 Å, PDB 4M84; green structure, nitrogen in cyan,oxygen in red, and sulfur in yellow) and 2 (PDB 3I7Ccarbon in orange andwater in pink). The key hydrogen bonds to the backbone oxygen of Glu129and NH of Tyr131 are the same in both scaffolds.

FIG. 2 illustrates compound 39 (1517) treatment of Toxoplasma infectionin mice.

FIG. 3 illustrates the effects of treatment with compound 39 in abeige/SCID mouse model of C. parvum infection.

FIG. 4 shows the table comparing the biological data of compound 39(1517) and compound 9 (1294).

DETAILED DESCRIPTION OF THE INVENTION

The following description provides specific details for a thoroughunderstanding of, and enabling description for, embodiments of thedisclosure. However, one skilled in the art will understand that thedisclosure may be practiced without these details. In other instances,well-known structures and functions have not been shown or described indetail to avoid unnecessarily obscuring the description of theembodiments of the disclosure.

In view of the present disclosure, the compounds described herein can beconfigured by the person of ordinary skill in the art to meet thedesired need. In general, the disclosed compounds provide improvementsin treatment of apicomplexan protozoan related diseases. For example, incertain aspects, the compounds of the disclosure are effective againstdisorders, including those caused by the infectious eukaryotic parasiteT. gondii, C. parvum and C. hominus, with low or no toxic side effects.In particular aspects, the compounds of the disclosure have little or norecombinant hERG (human Ether-à-go-go-Related Gene) binding, which whenhERG is inhibited is beneficial against long Q-T syndrome (i.e.,cardiotoxicity). In certain other aspects, the compounds of thedisclosure provide good oral bioavailability and stability in vivo.

In one embodiment, the compounds of formula (I) are those where R³ andR⁴ are independently selected from hydrogen and C₁₋₃ alkyl. In otherembodiments, R³ and R⁴ are independently selected from hydrogen andmethyl. In some other embodiments, one of R³ and R⁴ is hydrogen and theother is C₁₋₃ alkyl. In some other embodiments, one of R³ and R⁴ ishydrogen and the other is methyl. In certain embodiments, R³ and R⁴ areboth hydrogen.

In one embodiment, the compounds of formula (I) and any precedingembodiment are those where R⁵ and R⁶ are independently selected fromhydrogen and C₁₋₃ alkyl. In other embodiments, R⁵ and R⁶ areindependently selected from hydrogen and methyl. In some otherembodiments, one of R⁵ and R⁶ is hydrogen and the other is C₁₋₃ alkyl.In some other embodiments, one of R⁵ and R⁶ is hydrogen and the other ismethyl. In certain embodiments, R⁵ and R⁶ are both hydrogen.

Compounds of formula (I), in one embodiment, include those where R³, R⁴,R⁵ and R⁶ are all hydrogen.

Compounds of formula (I) and any previous embodiment include compoundswherein R² is C₁₋₆ alkyl, C₁₋₆ haloalkyl, —C₁₋₄ alkyl-R¹², C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, monocyclic heterocyclyl, monocyclicheteroaryl, or phenyl, wherein the alkyl, cycloalkyl, heterocyclyl,heteroaryl, and phenyl groups are each optionally substituted with oneor two R¹³ groups. In one embodiment, R² is C₁₋₆ alkyl, C₁₋₆ haloalkyl,or —C₁₋₄ alkyl-R¹², wherein the alkyl group is optionally substitutedwith one or two R¹³ groups. In another embodiment, R² is C₁₋₆ alkyl orC₁₋₆ haloalkyl, wherein the alkyl group is optionally substituted withone or two R¹³ groups. In another embodiment, R² is C₁₋₆ alkyl or —C₁₋₄alkyl-R¹², wherein the alkyl group is optionally substituted with one ortwo R¹³ groups.

Certain embodiments of the compounds of the disclosure include thosewhere R² is C₁₋₆ alkyl optionally substituted with one or two R¹³groups. In some embodiments, R² is C₁₋₆ alkyl optionally substitutedwith —OR or —NR₂. In other embodiments, R² is C₁₋₆ alkyl optionallysubstituted with —OH. In one embodiment of the disclosure, the compoundsare those where R² is unsubstituted C₁₋₆ alkyl. For example, R² may bemethyl, ethyl, propyl, isopropyl, butyl, secbutyl, isobutyl, andtertbutyl. In one embodiment, R² may be methyl, ethyl, propyl,isopropyl, butyl, secbutyl, isobutyl, or tertbutyl, each optionallysubstituted with one or two R¹³ groups. In a particular embodiment, R²is tent-butyl. In some other embodiments, R² is C₁₋₆ haloalkyl.

Other particularly useful compounds of formula (I) and any precedingembodiment are those where R² is —C₁₋₄ alkyl-R¹²optionally substitutedwith one or two R¹³ groups. In one embodiment, R¹² is —OR, —NR₂, —C(O)R,—C(O)OR, —C(O)NR₂, —S(O)₂R, phenyl, monocyclic heteroaryl, C₃₋₈cycloalkyl, or monocyclic heterocyclyl, wherein the aryl, heteroaryl,C₃₋₈ cycloalkyl, and heterocyclyl groups are each optionally substitutedby one, two, or three groups that are each independently halogen, cyano,nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR, —SR, —NR₂, —C(O)R, —C(O)OR,—C(O)NR₂, —S(O)₂R, —OC(O)R, —OC(O)OR, —OC(O)NR₂, —N(R)C(O)R,—N(R)C(O)OR, or —N(R)C(O)NR₂. In certain embodiment, R¹² is —OR, —NR₂,phenyl, monocyclic heteroaryl, C₃₋₈ cycloalkyl, or monocyclicheterocyclyl, wherein the aryl, heteroaryl, C₃₋₈ cycloalkyl, andheterocyclyl groups are each optionally substituted by one, two, orthree groups that are each independently halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆ haloalkyl, —OR, —SR, —NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,—S(O)₂R, —OC(O)R, —OC(O)OR, —OC(O)NR₂, —N(R)C(O)R, —N(R)C(O)OR, or—N(R)C(O)NR₂.

In another embodiment, R¹² is —OR, —SR, —NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,C₃₋₈ cycloalkyl, or monocyclic heterocyclyl, wherein the C₃₋₈cycloalkyl, and heterocyclyl groups are each optionally substituted byone, two, or three groups that are each independently halogen, cyano,nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR, —SR, —NR₂, —C(O)R, —C(O)OR,—C(O)NR₂, —S(O)₂R, —OC(O)R, —OC(O)OR, —OC(O)NR₂, —N(R)C(O)R,—N(R)C(O)OR, or —N(R)C(O)NR₂. In another embodiment, R¹² is —OR or —NR₂.Some embodiments include compounds of R² where R¹² is —OR. Some otherembodiments include compounds of R² where R¹² is C₃₋₈ cycloalkyl ormonocyclic heterocyclyl, both substituted as noted above.

In another embodiment, compounds of formula (I) and the aboveembodiments are those where R² is C₃₋₈ cycloalkyl or monocyclicheterocyclyl, each optionally substituted with one or two R¹³ groups. Insome embodiments, R² is C₃₋₈ cycloalkyl optionally substituted with oneor two R¹³ groups. In other embodiments, R² is monocyclic heterocyclyloptionally substituted with one or two R¹³ groups.

In another embodiment, compounds of formula (I) and the aboveembodiments are those where R² is hydrogen.

Other particularly useful compounds of formula (I) and any precedingembodiment are those wherein R¹ is one of the formulas:

As understood by one of skill in the art, each R⁷ may be in anyavailable position on the bicyclic ring. In some embodiments, R¹ is ofthe formula:

In another embodiment, R¹ is of the formula:

In some embodiments, R¹ is one of formulas:

In some other embodiments, R¹ is one of formulas:

In some other embodiments, R¹ is of the formula:

In another embodiment, R¹ is of the formula:

In yet another embodiment, R¹ is of the formula:

In some other embodiments, R¹ is of the formula:

In some other embodiments, R¹ is of the formula:

In some other embodiments, R¹ is of the formula:

As noted above, R⁸ may be hydrogen, halogen, cyano, nitro, C₁₋₆ alkyl,C₁₋₆ haloalkyl, or —Q—R^(8′). Thus, in one embodiment, compounds offormula (I) and any of the above embodiments include those where R⁸ ishydrogen, halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl. In oneembodiment, R⁸ is hydrogen, halogen, cyano, or nitro. In anotherembodiment, R⁸ is hydrogen, halogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl. Inyet another embodiment, R⁸ is hydrogen or halogen. In particularembodiments, R⁸ is hydrogen.

Another embodiment provides compounds of formula (I) and any of theabove embodiments include those where R⁸ is —Q—R^(8′).

Embodiments of the compounds of the disclosure include those where, whenR⁸ is —Q—R^(8′), then:

-   Q is —O—, —S—, —NH—, or —N(C₁₋₆ alkyl);-   R^(8′) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₈    cycloalkyl, heterocyclyl, aryl, aryl C₁₋₆ alkyl, heteroaryl, or    heteroaryl C₁₋₆ alkyl, wherein the alkyl, aryl, arylalkyl,    heteroaryl, and heteroarylalkyl are optionally substituted with one,    two, three, or four groups that are each independently halogen,    cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR¹⁴, —SR¹⁴, —N(R¹⁴)₂,    —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —S(O)₂R¹⁴, —OC(O)R¹⁴, —OC(O)OR¹⁴,    —OC(O)N(R¹⁴)₂, —N(R¹⁴)C(O)R¹⁴, —N(R¹⁴)C(O)OR¹⁴, —N(R¹⁴)C(O)OR¹⁴, or    —N(R¹⁴)C(O)N(R¹⁴)₂, wherein each R¹⁴ is independently hydrogen or    C₁₋₆ alkyl.-   In other embodiments, Q is —O—, —S—, —NH—, or —N(C₁₋₆ alkyl)—; and-   R^(8′) is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl,    heterocyclyl, aryl, arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆    alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, and    heteroarylalkyl are optionally substituted with one, two, three, or    four groups that are each independently halogen, cyano, nitro, C₁₋₆    alkyl, C₁₋₆ haloalkyl, OR¹⁴, —SR¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴,    —C(O)N(R¹⁴)₂, —S(O)₂R¹⁴, —OC(O)R¹⁴, —OC(O)OR¹⁴, —OC(O)N(R¹⁴)₂,    —N(R¹⁴)C(O)R¹⁴, —N(R¹⁴)C(O)OR¹⁴, or —N(R¹⁴)C(O)N(R¹⁴)₂, wherein each    R¹⁴ is independently hydrogen or C₁₋₆ alkyl.

Embodiments of the compounds of the disclosure include those where R⁸ is—O—R^(8′), —NH R^(8′), or —N(C₁₋₆ alkyl)R^(8′). In some otherembodiments, R⁸ is —O—R^(8′).

Other embodiments provide compounds where, according to any precedingembodiment, R^(8′) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆haloalkyl, or C₃₋₈ cycloalkyl, wherein the alkyl moieties are optionallysubstituted with one, two, three, or four groups that are eachindependently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR¹⁴,—SR¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —S(O)₂R¹⁴,—OC(O)OR¹⁴, —OC(O) N(R¹⁴)₂, —N(R¹⁴)C(O)R¹⁴, —N(R¹⁴)C(O)OR¹⁴, or—N(R¹⁴)C(O)N(T¹⁴)², wherein each R¹⁴ is independently hydrogen or C₁₋₆alkyl. In some other embodiments, R^(8′) is C₁₋₆ alkyl, C₁₋₆ haloalkyl,or C₃₋₈ cycloalkyl, wherein the alkyl moieties are optionallysubstituted with one, two, three, or four groups that are eachindependently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR¹⁴,—SR¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —S(O)₂R¹⁴,—OC(O)R¹⁴, —OC(O)OR¹⁴, —OC(O)N(R¹⁴)₂, —N(R¹⁴)C(O)R¹⁴, —N(R¹⁴)C(O)OR¹⁴,or —N(R¹⁴)C(O)N(R¹⁴)₂, wherein each R¹⁴ is independently hydrogen orC₁₋₆ alkyl. In additional embodiments, R^(8′) is C₁₋₆ alkyl optionallysubstituted with one, two, three, or four groups that are eachindependently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR¹⁴,—SR¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —S(O)₂R¹⁴,—OC(O)OR¹⁴, —OC(O) N(R14)₂, —N(R¹⁴)C(O)R¹⁴, —N(R¹⁴) C(O)OR¹⁴, or—N(R¹⁴)C(O)N(R¹⁴)₂, wherein each R¹⁴ is independently hydrogen or C₁₋₆alkyl.

Another embodiment provides compounds of any of the above embodimentsinclude those where R^(8′) is C₁₋₆ alkyl optionally substituted withone, two, three, or four groups that are each independently halogen,—OR14, —SR¹⁴, —N(R¹⁴)2, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂, or —S(O)₂R¹⁴,wherein each R¹⁴ is independently hydrogen or C₁₋₆ alkyl. Embodiments ofthe disclosed compounds include those where R^(8′) is unsubstituted C₁₋₆alkyl.

Embodiments of the compounds of the disclosure include those whereR^(8′) is methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, ort-butyl. In some embodiments, R^(8′) is ethyl.

In one embodiment, R⁸ is —O—R^(8′), wherein R^(8′) is C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, arylC₁₋₆ alkyl, or heteroarylC₁₋₆ alkyl,each optionally substituted as noted above.

Other embodiments provide compounds where R⁸ is —O—R^(8′), and R^(8′) isC₁₋₆ alkyl or C₁₋₆ haloalkyl, each optionally substituted as notedabove. In one embodiment, R⁸ is C₁₋₆ alkoxy optionally substituted asnoted above. For example, R⁸ may be methoxy, ethoxy, n- or i-propoxy, orn-, i-, or t-butoxy (each optionally substituted as noted above). In oneembodiment, R⁸ is ethoxy.

Another embodiment provides compounds of formula (I) and any of theabove embodiments where R⁸ is hydrogen, halogen, C₁₋₆ alkyl, or C₁₋₆haloalkyl. In one embodiment, R⁸ is C₁₋₆ alkyl or C₁₋₆ haloalkyl. Inanother embodiment, R⁸ is hydrogen or halogen. In yet anotherembodiment, R⁸ is halogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

Other particularly useful compounds of formula (I) and any precedingembodiment are those wherein R¹ is one of the formulas:

In another embodiment, R¹ is of the formula:

In another embodiment, R¹ is of the formula:

Another embodiment provides compounds of formula (I) and any of theabove embodiments where R⁷, when present, is at any available positionon the ring and independently selected from halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆ haloalkyl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)₂, —C(O)R¹⁰, —C(O)N(R¹⁰)₂,—S(O)₂R¹⁰, and —N(R¹⁰)C(O)R¹⁰, wherein each R¹° is independentlyhydrogen or C₁₋₆ alkyl. In another embodiment, R⁷, when present, isindependently selected from halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆haloalkyl, —OR¹⁰, —N(R¹⁰)₂, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)N(R¹⁰)₂. Inanother embodiment, R⁷, when present, is independently selected fromhalogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR¹⁰, and —N(R¹⁰)₂.In another embodiment, R⁷, when present, is independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR¹⁰, and —N(R¹⁰)₂. In another embodiment,R⁷, when present, is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

Other embodiments of the disclosure according to any precedingembodiments provide compounds where each R⁷ when present isindependently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR¹⁰,—SR¹⁰, —N(R¹⁰)₂, —C(O)R¹⁰, —C(O)OR¹⁰, or —C(O)N(R¹⁰)₂, wherein each R¹⁰is independently hydrogen or C₁₋₆ alkyl. In one embodiment, each R⁷ isindependently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR¹⁰,or —N(R¹⁰)₂, wherein each R¹⁰ is independently hydrogen or C₁₋₆ alkyl.In another embodiment, each R⁷ is independently halogen, cyano, nitro,C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

Another embodiment provides compounds of formula (I) and any of theabove embodiments where n is 0 or 1. In one embodiments, n is 0. Inother embodiments, n is 1.

Other particularly useful compounds of formula (I) and any precedingembodiment are those wherein R¹ is one of the formulas:

As understood by one of skill in the art, each R⁷ may be in anyavailable position on the bicyclic ring. In one embodiment, R¹ is one ofthe formulas:

In another embodiment, R¹ is one of the formulas:

In another embodiment, R¹ is of the formula:

Other embodiments provide compounds where, according to any precedingembodiment, each R⁹ is independently hydrogen or C₁₋₄ alkyl. In someembodiments, each R⁹ is independently hydrogen or methyl.

Clinical toxoplasmosis is caused by the actively dividing tachyzoiteform of the parasite, which exits its host cell and invades a new cellevery few days. TgCDPK1 has a unique ATP-binding site with a smallgatekeeper residue, as opposed to the large gatekeeper residues presentin mammalian protein kinases. This key difference in gatekeeper residuesbetween mammalian kinases and TgCDPK1 allowed use of bumped kinaseinhibitors (BKIs) to selectively inhibit TgCDPK1 without untowardeffects on the mammalian host cell.

Accordingly, the disclosure provides methods for treating anapicomplexan protozoan related disease comprising providing to a patientin need of such treatment a therapeutically effective amount of either(i) one or more of compounds of the disclosure or (ii) a pharmaceuticalcomposition comprising one or more of compounds of the disclosure and apharmaceutically acceptable excipient, carrier, or diluent. In oneembodiment, the compound of the disclosure is according to of theformula (I) as defined above, or any embodiment thereof.

One embodiment of the present disclosure provide a method of treating asubject in need of treatment for an apicomplexan-related diseasecomprising administering an effective amount of one or more of compoundof the disclosure, that inhibits the activity of an apicomplexan calciumdependent protein kinase (CDPK).

Particular embodiments of the present disclosure provide a method oftreating cryptosporidiosis in a subject comprising administering aneffective amount of one or more of compounds of the disclosure, thatinhibits the activity of Cryptosporidium parvum and C. hominus calciumdependent protein kinase 1 (CpCDPK1).

Other particular embodiments of the present disclosure provide a methodof treating cryptosporidiosis in a subject comprising administering aneffective amount of one or more of compounds of the disclosure, thatinhibits the activity of T. gondii, calcium dependent protein kinase 1(TgCDPK1).

Optionally, the compound of the disclosure, can be administered incombination with a second agent, such as agents specific for use againstthe specific apicomplexan-related disorder being treated.

In one embodiment, the apicomplexan protozoan related disease istoxoplasmosis. As understood by one of ordinary skill in the art,toxoplasmosis can encompass a number of pathologies, including, but notlimited to, encephalitis, retinitis, lymphadenopathy, disseminateddisease, and hepatitis. Toxoplasmosis infects most genera ofwarm-blooded animals, including humans, but the primary host is thefelid (cat) family.

Cats are the definitive host for the Toxoplasma organism. Infection withthis protozoan parasite is fairly common, but actual disease caused bythis parasite is relatively rare in cats. Cats can become infected byToxoplasma by eating any of the three infective stages of the parasites.The most common route of infection is probably by ingestion of tissuecysts in infected prey or in other raw meat. Toxoplasma multiply in thesmall intestines and in approximately two to three weeks the oocysts areexcreted in the infected cat's feces. In another example, cats may betreated prophylactically for toxoplasmosis (e.g., a gastrointestinalinfection) provided by providing a therapeutically effective amount ofone or more of compounds of the disclosure or to eliminate the chancethat they would shed infectious Toxoplasmodia oocyts and infect theirowners. In another embodiment, infected cats may be treated by providinga therapeutically effective amount of one or more of compounds of thedisclosure to treat toxoplasmosis. As will be understood by those ofskill in the art, similar prophylactic and therapeutic methods forlimiting development of or treating toxoplasmosis can be used in anyanimal that can be infected by Toxoplasma sp.

Animals are infected by eating infected meat, by ingestion of feces of acat that has itself recently been infected, or by transmission frommother to fetus. While cats are often blamed for spreadingtoxoplasmosis, contact with raw meat is a more significant source ofhuman infections in many countries, and fecal contamination of hands isa greater risk factor. Infection has two stages (1) acute toxoplasmosis;and (2) latent toxoplasmosis. During acute toxoplasmosis, symptoms areoften influenza-like: swollen lymph nodes, or muscle aches and painsthat last for a month or more. Rarely, a patient with a fullyfunctioning immune system may develop eye damage from toxoplasmosis.Young children (15 years old or younger) and immunocompromised patients,such as those with HIV/AIDS, those taking certain types of chemotherapy,or those who have recently received an organ transplant, may developsevere toxoplasmosis. In an embodiment, a young child can be 14 yearsold or younger; or 13 years old or younger; or 12 years old or younger;or 11 years old or younger; or 10 years old or younger; or 9 years oldor younger; or 8 years old or younger; or 7 years old or younger; or 6years old or younger; or 5 years old or younger; or 4 years old oryounger; or 3 years old or younger; or 2 years old or younger; or 1 yearold or younger. This can cause damage to the brain (encephalitis) or theeyes (necrotizing retinochoroiditis). Infants infected via placentaltransmission may be born with either of these problems, or with nasalmalformations, although these complications are rare in newborns. Inmost immuno-competent patients, the infection enters a latent phase,during which only bradyzoites are present, forming cysts in nervous andmuscle tissue. Most infants who are infected while in the womb have nosymptoms at birth but may develop symptoms later in life. The mostcommon current therapy for toxoplasmosis is sulfadiazine/pyrimethaminecombination therapy, but therapy is often limited by allergic reactionsto the sulfa component, anemia and pancytopenia induced by blocking thefolate pathway. When sulfadiazine cannot be used, clindamycin may becombined with pyrimethamine but most experts feel it does not work aswell as sulfadiazine. Spiramycin has been used for toxoplasmosis duringpregnancy but has issues with low efficacy and is no longer available inthe United States. Thus few therapeutic alternatives are available.

In another embodiment, the apicomplexan protozoan related disease iscryptosporidiosis. Cryptosporidiosis is caused by infection with thesingle-celled parasite (not bacterium) Cryptosporidium parvum. Thisparasite is found in many mammals including lambs, calves, goat kids,piglets and humans. Research so far has shown two basic types, thebovine type which affects most species, and a second human type whichcauses disease in humans only. Outbreaks of human disease, where largenumbers of people are affected, are usually water-borne and usuallyassociated with the bovine type of cryptosporidium. Individual sporadiccases of cryptosporidiosis in humans are mostly (around 60%) associatedwith the human type of cryptosporidium.

Cryptosporidiosis affects the intestines of mammals and is typically anacute short-term infection. It is spread through the fecal-oral route,often through contaminated water; the main symptom is self-limitingdiarrhea in people with intact immune systems. In immunocompromisedindividuals, such as HIV/AIDS patients, the symptoms are particularlysevere and often fatal. Cryptosporidium is the organism most commonlyisolated in HIV positive patients presenting with diarrhea.Cryptosporidiosis is one of the most common waterborne diseases and isfound worldwide. The parasite is transmitted by environmentally hardymicrobial cysts (oocysts) that, once ingested, exist in the smallintestine and result in an infection of intestinal epithelial tissue.Infection is through contaminated material such as earth, water,uncooked or cross-contaminated food that has been in contact with thefeces of an infected individual or animal. It is especially prevalentamongst those in regular contact with bodies of fresh water includingrecreational water such as swimming pools. Other potential sourcesinclude insufficiently treated or insufficiently filtered watersupplies, contaminated food, or exposure to feces. Symptoms appear fromtwo to ten days after infection, and last for up to two weeks or more.In immuno-competent people, the disease can be asymptomatic or causeacute diarrhea or persistent diarrhea that can last for a few weeks.There is often stomach pain or cramping and a low fever. Other symptomsmay include nausea, vomiting, malabsorption, and dehydration.Individuals who are asymptomatic (have no symptoms) are neverthelessinfective. Immunocompromised people, as well as very young or very oldpeople, can develop a more severe form of cryptosporidiosis. WhenCryptosporidium spreads beyond the intestine, as it can predominantly inpatients with AIDS, it can reach the lungs, middle ear, pancreas, andstomach. Thus, one symptom is pain in the right upper quadrant. Theparasite can infect the biliary tract, causing biliarycryptosporidiosis. This can result in cholecystitis and cholangitis.Current treatment is symptomatic, with fluid rehydration, electrolytecorrection and management of any pain. Nitazoxanide has beenFDA-approved for treatment of diarrhea caused by Cryptosporidium inpeople with healthy immune systems and is available by prescription,however it only shortens the duration of diarrhea by a couple of days.The effectiveness of nitazoxanide in immunosuppressed individuals isunclear and multiple trials have shown no benefit.

The compounds described herein may have use in other apicoplexaprotozoan related diseases, such as coccidiosis or eimeriosis caused byEimeria spp., cause infections and disease in poultry; which causesBabesiosis which is caused by Babesia spp. and results in a malaria-likedisease, and malaria in humans and animals caused by Plasmodium spp.

As used herein, the term “subject”, “individual,” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, birds, swine, horses,livestock (e.g., pigs, sheep, goats, cattle), primates or humans.

As used here, a subject “in need thereof” refers to a subject that hasthe disorder or disease to be treated or is predisposed to or otherwiseat risk of developing the disease or disorder.

As used here, the terms “treatment” and “treating” means:

-   (i) inhibiting the progression the disease;-   (ii) prophylactic use for example, preventing or limiting    development of a disease, condition or disorder in an individual who    may be predisposed or otherwise at risk to the disease, condition or    disorder but does not yet experience or display the pathology or    symptomatology of the disease;-   (iii) inhibiting the disease; for example, inhibiting a disease,    condition or disorder in an individual who is experiencing or    displaying the pathology or symptomatology of the disease, condition    or disorder;-   (iv) ameliorating the referenced disease state, for example,    ameliorating a disease, condition or disorder in an individual who    is experiencing or displaying the pathology or symptomatology of the    disease, condition or disorder (i.e., reversing or improving the    pathology and/or symptomatology) such as decreasing the severity of    disease; or-   (v) eliciting the referenced biological effect.

In various preferred embodiments, the individual may beimmunocompromised (having an immune system that has been impaired bydisease or treatment, such as an HIV infected patient, and AIDS patient,or a patient receiving chemotherapy or an organ transplant), a pregnantfemale, fifteen years old or younger, fifty-five years old or older,exposed to contaminated water supplies, and/or exposed to other sourcesof contamination (fecal matter, blood transfusion, earth, food, etc.)The methods may further comprise administering the compounds disclosedherein to subjects at risk of acquiring an apicomplexan-related disease,such as those with compromised immune systems or that are extremelyyoung in high risk areas.

In other embodiments, the compounds described herein can be used inprophylactic manner. Cryptosporidiosis is usually seen in calves betweenone and two weeks of age and presents with diarrhea, colic and pain,depression, loss of appetite, and weight loss. Thus, in one embodiment,calves may be treated prophylactically by providing an effective amountof one or more of compounds of the disclosure to limit the contractionor transmission of cryptosporidiosis. In a preferred embodiment, theadministering is done within the first 7-8 days after birth (day 1, 2,3, 4, 5, 6, 7, or 8) when calves are most susceptible to Cryptosporidiainfection. Such treatments may be repeated as necessary as would beunderstood by one skilled in the art.

In another embodiment, infected cattle may be treated by providing atherapeutically effective amount of one or more of compounds of thedisclosure to treat cryptosporidiosis. Such treatments may be repeatedas necessary as would be understood by one skilled in the art. In thisembodiment, the compounds of the invention may be administered togetherwith electrolytes if cattle become dehydrated. If disease is severe,halfuginone can be used in combination with the compounds of theinvention to reduce disease severity and prevent spread to otheranimals.

In another example, lambs are susceptible to cryptosporidiosis and maybe provided a therapeutically effective amount of one or more ofcompounds of the disclosure to limit the contraction or transmission ofcryptosporidiosis.

In another example, any or all members of a herd (e.g., cattle, goats,lambs, etc.), may be provided a therapeutically effective amount of oneor more of compounds of the disclosure to limit the contraction ortransmission of toxoplasmosis or cryptosporidiosis or to rid the herd ofcattle of toxoplasmosis or cryptosporidiosis.

In another embodiment, goat kids may be treated prophylactically byproviding an effective amount of one or more of compounds of thedisclosure to limit the contraction or transmission ofcryptosporidiosis. In a preferred embodiment, the administering is donewithin the first 7-8 days after birth (day 1, 2, 3, 4, 5, 6, 7, or 8)when kids are most susceptible to cryptosporidiosis. Such treatments maybe repeated as necessary as would be understood by one skilled in theart. The extent to which a kid is infected seems to be dependent on itsage and immune status. Younger animals are much more susceptible toinfection than adults. In studies done with lambs, five-day-old lambshad diarrhea for 9-10 days and suffered from a high rate of mortality.Sixty-day-old lambs showed no symptoms when they were infected, andadult sheep completely resisted infection. There is an indication thatadults develop an immunity to Cryptosporidium, yet this immunity doesnot seem to be passed to their offspring.

Immune-depressed goats are very susceptible to the disease. This refersto the total immune status, not just protection from cryptosporidiosis.Many situations can cause animals to lack immunity. Animals with severeinfections are more susceptible to secondary infections. The most commonproblem with kids is receiving a deficient amount of colostralantibodies following birth. Whether caused by disease, an imbalancedration or improper management, animals lacking adequate immunity aremuch more susceptible to cryptosporidiosis.

In another embodiment, infected goats may be treated by providing atherapeutically effective amount of one or more of compounds of thedisclosure to treat cryptosporidiosis. In a preferred embodiment, thegoat is a kid.

In another example, pigs are susceptible to cryptosporidiosis and may beprovided a therapeutically effective amount of one or more of compoundsof the disclosure to limit the contraction or transmission ofcryptosporidiosis. In a preferred embodiment, the administering is donewithin the first 21 days after birth (day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21) when piglets are mostsusceptible to cryptosporidiosis and/or most likely

In another embodiment, infected pigs may be treated by providing atherapeutically effective amount of one or more of compounds of thedisclosure to treat cryptosporidiosis. In a preferred embodiment, thepig is a piglet.

In another example, birds, such as turkeys and chickens, are susceptibleto cryptosporidiosis and may be provided an effective amount of one ormore of compounds of the disclosure to prevent the contraction ortransmission of cryptosporidiosis. In particular, Cryptosporidiumbaileyi can cause respiratory disease in chickens and turkeys. The samespecies causes infections of the hindgut and cloacal bursa in chickens,turkeys, and ducks. C. meleagridis also infects both species. A furtherspecies causes respiratory disease in quail. The oocysts are excretedready sporulated in the faeces and infection occurs by inhalation andingestion. Signs of cryptosporidiosis in poultry include snick, cough,swollen sinuses, low weight gain, and diarrhea. In another embodiment,infected birds may be treated by providing a therapeutically effectiveamount of one or more of compounds of the disclosure to treatcryptosporidiosis.

In another example, birds, such as turkeys and chickens, are susceptibleto coccidiosis or eimeriosis due to Eimeria infections and may beprovided an effective amount of one or more of compounds of thedisclosure to limit the contraction or transmission of coccidiosis, aparasitic disease caused by the development and multiplication ofcoccidia in the epithelial cells of the intestine. Eimeria infectionsare ubiquitous; they are found wherever chickens or turkeys are reared(traditional, industrial, label or organic/bio farms). Particularstrains of Eimeria known to infect birds include, but are not limitedto, Eimeria acervuline, Eimeria adenoeides, Eimeria brunette, Eimeriacolchici, Eimeria curvata, Eimeria dispersa, Eimeria duodenali, Eimeriafraterculae, Eimeria gallopavonis, Eimeria praecox, Eimeria maxima,Eimeria meleagrimitis, Eimeria mitis, Eimeria necatrix, Eimeriaphasiani, Eimeria procera, and Eimeria tenella. In another embodiment,infected birds may be treated by providing a therapeutically effectiveamount of one or more of compounds of the disclosure to treatcoccidiosis.

In another example, mammals, such as goats, sheep, llamas, alpacas,cattle, rabbits, and mice, are susceptible to coccidiosis or eimeriosisand may be provided an effective amount of one or more of compounds ofthe disclosure to limit the contraction or spreading of Eimeria.Particular strains of Eimeria known to infect mammals include, but arenot limited to, Eimeria ahsata, Eimeria alabamensis, Eimeria alijevi,Eimeria apsheronica, Eimeria arloingi, Eimeria arundeli, Eimeriabakuensis, Eimeria bovis, Eimeria cameli, Eimeria caprina, Eimeriacaprovina, Eimeria christenseni, Eimeria clethrionomyis, Eimeriacoecicola, Eimeria contorta, Eimeria couesii, Eimeria crandallis,Eimeria dammahensis, Eimeria dowleri, Eimeria exigua, Eimeriafalciformis, Eimeria farasanii, Eimeria ferrisi, Eimeria flavescens,Eimeria gallatii, Eimeria granulosa, Eimeria hirci, Eimeriaintestinalis, Eimeria irresidua, Eimeria intricate, Eimeria jolchijevi,Eimeria krijgsmanni, Eimeria larimerensis, Eimeria macusaniensis,Eimeria magna, Eimeria marconii, Eimeria media, Eimeria melanuri,Eimeria myoxi, Eimeria nagpurensis, Eimeria ninakohlyakimovae, Eimeriaovinoidalis, Eimeria pallida, Eimeria palustris, Eimeria papillata,Eimeria perforans, Eimeria phocae, Eimeria pileata, Eimeria pipistrellu,Eimeria piriformis, Eimeria prionotemni, Eimeria punctate, Eimeriaroobroucki, Eimeria saudiensis, Eimeria sealanderi, Eimeria separate,Eimeria stiedae, Eimeria ursini, Eimeria vermiformis, Eimeriaweybridgensis, Eimeria wobati, and Eimeria zuernii. In anotherembodiment, infected mammals may be treated by providing atherapeutically effective amount of one or more of compounds of thedisclosure to treat coccidiosis.

The usual age range for animals suffering from coccidiosis or eimeriosisis from three weeks to one year of age, but cattle remain susceptible tococcidiosis or eimeriosis throughout their lives or until they developacquired immunity. The susceptibility of the animals is influenced bynutritional status (colostrum supply), stress (overstocking, transport,climate, hygiene, etc.), immune status and the occurrence of concurrentdiseases.

Infections with multiple Eimeria species (pathogenic and non-pathogenic)are common in real life situations. The most important species relatedto the clinical manifestation of the disease in the stable are Eimeriabovis and Eimeria zuernii, although other pathogenic coccidia speciesmay also affect the cattle in the stables, such as Eimeria alabamensis(animals fed on contaminated hay), which is commonly associated withdiarrheic problems in animals that are released to pasture.

“Carrier hosts” shed relatively fewer oocysts and the susceptible“multiplier hosts” pick up the infection and shed many-fold oocysts intothe environment. Exposure to multiplier hosts leads to subclinical ormildly clinical infection in animals exposed to a large number ofoocysts in the environment. Calves exposed to a large number of oocystsare likely to develop severe coccidiosis. In feedlots where few oocystsare present, stress factors such as weaning, diet, temperature extremesand other variables may make the calves more susceptible to infectionand under such conditions the reproductive potential of coccidia in thegut greatly increases.

In goats, although the infection can occur in any goat herd raised undersemi and intensive management practices, it is most frequently observedin kids 2 to 4 weeks postweaning The infection occurs by ingesting thepathogenic sporulated oocyst (sporulated is a form of resistance of theCoccidia). Oocysts can be found in the water or in feed suppliescontaminated with feces. Once ingested, oocysts penetrate the cellslining the intestine where they go through several stages of developmentand cause inflammation and destruction of intestinal cells. Stress isthe predisposing factor in kids during the postweaning period. Outbreakscan occur during stressful conditions such as after shipping or whenanimals are relocated. Outbreaks can also occur during sudden weatherchanges, after a change in concentrated feed practices, when animals arerecovering from a disease, or in worm burden cases. Although coccidiosiscan occur year around, a higher incidence occurs during postweaning

The compounds disclosed herein can be used to treat coccidiosis incombination with standard treatments such as, but not limited to,replacing fluids by administering liquid nutritional supplement orallyby nipple bottle until the animal is rehydrated. Animals that have lost5 percent of their body weight may require intravenous (IV) and/orelectrolyte therapy. Treatment may include IV or subcutaneously (SC)fluid therapy with a physiologically balanced electrolyte such asRinger's, Plasmalyte-A, or Normosol-R. Administer the solution (2 to 5milliliters per pound) one to three times daily until the animal isrehydrated. Sulfas such as Albon™, Sulmet™, or Di-Methox™, can also bemixed in the drinking water or as a drench for individual goats. Analternative is CORID™ (amprolium).

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician, which includes one or more of thefollowing: (1) preventing the disease; for example, preventing adisease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease; (2) inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder; and (3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

The pharmaceutical compositions described herein generally comprise acombination of one or more of compounds described herein and apharmaceutically acceptable carrier, diluent, or excipient. Suchcompositions are substantially free of non-pharmaceutically acceptablecomponents, i.e., contain amounts of non-pharmaceutically acceptablecomponents lower than permitted by US regulatory requirements at thetime of filing this application. In some embodiments of this aspect, ifthe compound is dissolved or suspended in water, the composition furtheroptionally comprises an additional pharmaceutically acceptable carrier,diluent, or excipient. In one embodiment, the pharmaceuticalcompositions described herein are solid pharmaceutical compositions(e.g., tablet, capsules, etc.).

These compositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal, intranasal,epidermal and transdermal), ocular, oral or parenteral. Methods forocular delivery can include topical administration (eye drops),subconjunctival, periocular or intravitreal injection or introduction byballoon catheter or ophthalmic inserts surgically placed in theconjunctival sac. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

Also, pharmaceutical compositions can contain, as the active ingredient,one or more of the compounds described herein above in combination withone or more pharmaceutically acceptable carriers. In making thecompositions described herein, the active ingredient is typically mixedwith an excipient, diluted by an excipient or enclosed within such acarrier in the form of, for example, a capsule, sachet, paper, or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions described herein can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein. When referring to these preformulationcompositions as homogeneous, the active ingredient is typicallydispersed evenly throughout the composition so that the composition canbe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation is thensubdivided into unit dosage forms of the type described above containingfrom, for example, 0.1 to about 500 mg of the active ingredient of acompound described herein.

The tablets or pills can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permit the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

The liquid forms in which the compounds and compositions can beincorporated for administration orally or by injection include aqueoussolutions, suitably flavored syrups, aqueous or oil suspensions, andflavored emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil, or peanut oil, as well as elixirs and similarpharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds can vary according to, forexample, the particular use for which the treatment is made, the mannerof administration of the compound, the health and condition of thepatient, and the judgment of the prescribing physician. The proportionor concentration of a compound described herein in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. For example, the compounds described herein can beprovided in an aqueous physiological buffer solution containing about0.1 to about 10% w/v of the compound for parenteral administration. Sometypical dose ranges are from about 1 μg/kg to about 1 g/kg of bodyweight per day. In some embodiments, the dose range is from about 0.01mg/kg to about 100 mg/kg of body weight per day. The dosage is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected,formulation of the excipient, and its route of administration. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test systems.

The compounds described herein can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Definitions

Unless the context clearly requires otherwise, throughout thedescription and the claims, the words ‘comprise’, ‘comprising’, and thelike are to be construed in an inclusive sense as opposed to anexclusive or exhaustive sense; that is to say, in the sense of“including, but not limited to”. Words using the singular or pluralnumber also include the plural or singular number, respectively.Additionally, the words “herein,” “above” and “below” and words ofsimilar import, when used in this application, shall refer to thisapplication as a whole and not to any particular portions of thisapplication.

Terms used herein may be preceded and/or followed by a single dash, “–”,or a double dash, “=”, to indicate the bond order of the bond betweenthe named substituent and its parent moiety; a single dash indicates asingle bond and a double dash indicates a double bond. In the absence ofa single or double dash it is understood that a single bond is formedbetween the substituent and its parent moiety; further, substituents areintended to be read “left to right” unless a dash indicates otherwise.For example, C₁-C₆alkoxycarbonyloxy and —OC(O)C₁-C₆alkyl indicate thesame functionality; similarly arylalkyl and -alkylaryl indicate the samefunctionality.

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons, unless otherwise specified,and containing at least one carbon-carbon double bond. Representativeexamples of alkenyl include, but are not limited to, ethenyl,2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl,2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and3,7-dimethylocta-2,6-dienyl.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms, unless otherwisespecified. Representative examples of alkyl include, but are not limitedto, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl. When an “alkyl” group is a linking group between two othermoieties, then it may also be a straight or branched chain; examplesinclude, but are not limited to —CH₂—, —CH₂CH₂—, —CH₂CH₂CHC(CH₃)—,—CH₂CH(CH₂CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butyryl, 2-pentynyl, and 1-butyryl.

The term “aryl,” as used herein, means a phenyl (i.e., monocyclic aryl),a bicyclic ring system containing at least one phenyl ring or anaromatic bicyclic ring containing only carbon atoms in the aromaticbicyclic ring system or a multicyclic aryl ring system, provided thatthe bicyclic or multicyclic aryl ring system does not contain aheteroaryl ring when fully aromatic. The bicyclic aryl can be azulenyl,naphthyl, or a phenyl fused to a monocyclic cycloalkyl, a monocycliccycloalkenyl, or a monocyclic heterocyclyl. The bicyclic aryl isattached to the parent molecular moiety through any carbon atomcontained within the phenyl portion of the bicyclic system, or anycarbon atom with the napthyl or azulenyl ring. The fused monocycliccycloalkyl or monocyclic heterocyclyl portions of the bicyclic aryl areoptionally substituted with one or two oxo and/or thia groups.Representative examples of the bicyclic aryls include, but are notlimited to, azulenyl, naphthyl, dihydroinden-1-yl, dihydroinden-2-yl,dihydroinden-3-yl, dihydroinden-4-yl, 2,3-dihydroindol-4-yl,2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl,inden-1-yl, inden-2-yl, inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl,dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-1-yl,5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl,2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl,2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl,benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl,2H-chromen-2-on-5-yl, 2H-chromen-2-on-6-yl, 2H-chromen-2-on-7-yl,2H-chromen-2-on-8-yl, isoindoline-1,3-dion-4-yl,isoindoline-1,3-dion-5-yl, inden-1-on-4-yl, inden-1-on-5-yl,inden-1-on-6-yl, inden-1-on-7-yl, 2,3-dihydrobenzo [b][1,4]diox an-5-yl,2,3-dihydrobenzo [b][1,4]dioxan-6-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-5-yl, 2H-benzo[b][1,4]oxazin3 (4H)-on-6-yl,2H-benzo[b][1,4]oxazin3 (4H)-on-7-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-8-yl, benzo[d]oxazin-2(3H)-on-5-yl, benzo[d]oxazin-2(3H)-on-6-yl, benzo [d]oxazin-2 (3H)-on-7-yl, benzo[d]oxazin-2(3H)-on-8-yl, quinazolin-4(3H)-on-5-yl,quinazolin-4(3H)-on-6-yl, quinazolin-4(3H)-on-7-yl,quinazolin-4(3H)-on-8-yl, quinoxalin-2(1H)-on-5-yl,quinoxalin-2(1H)-on-6-yl, quinoxalin-2(1H)-on-7-yl,quinoxalin-2(1H)-on-8-yl, benzo [d]thiazol-2(3H)-on-4-yl, benzo[d]thiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, and,benzo[d]thiazol-2(3H)-on-7-yl. In certain embodiments, the bicyclic arylis (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 memberedmonocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl,cycloalkenyl, and heterocyclyl groups are optionally substituted withone or two groups which are independently oxo or thia. Multicyclic arylgroups are a phenyl ring (base ring) fused to either (i) one ring systemselected from the group consisting of a bicyclic aryl, a bicycliccycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or(ii) two other ring systems independently selected from the groupconsisting of a phenyl, a bicyclic aryl, a monocyclic or bicycliccycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic orbicyclic heterocyclyl, provided that when the base ring is fused to abicyclic cycloalkyl, bicyclic cycloalkenyl, or bicyclic heterocyclyl,then the base ring is fused to the base ring of the a bicycliccycloalkyl, bicyclic cycloalkenyl, or bicyclic heterocyclyl. Themulticyclic aryl is attached to the parent molecular moiety through anycarbon atom contained within the base ring. In certain embodiments,multicyclic aryl groups are a phenyl ring (base ring) fused to either(i) one ring system selected from the group consisting of a bicyclicaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclicheterocyclyl; or (ii) two other ring systems independently selected fromthe group consisting of a phenyl, a monocyclic cycloalkyl, a monocycliccycloalkenyl, and a monocyclic heterocyclyl, provided that when the basering is fused to a bicyclic cycloalkyl, bicyclic cycloalkenyl, orbicyclic heterocyclyl, then the base ring is fused to the base ring ofthe a bicyclic cycloalkyl, bicyclic cycloalkenyl, or bicyclicheterocyclyl. Examples of multicyclic aryl groups include but are notlimited to anthracen-9-yl and phenanthren-9-yl.

The term “arylalkyl” and “-alkylaryl” as used herein, means an arylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofarylalkyl include, but are not limited to, benzyl, 2-phenylethyl,3-phenylpropyl, and 2-naphth-2-ylethyl.

The terms “cyano” and “nitrile” as used herein, mean a —CN group.

The term “cycloalkyl” as used herein, means a monocyclic, bicyclic, or amulticyclic cycloalkyl ring system. Monocyclic ring systems are cyclichydrocarbon groups containing from 3 to 8 carbon atoms, where suchgroups can be saturated or unsaturated, but not aromatic. In certainembodiments, cycloalkyl groups are fully saturated. Examples ofmonocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fusedbicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkylring where two non-adjacent carbon atoms of the monocyclic ring arelinked by an alkylene bridge of between one and three additional carbonatoms (i.e., a bridging group of the form —(CH₂)_(w)—, where w is 1, 2,or 3). Representative examples of bicyclic ring systems include, but arenot limited to, bicyclo[3.1.1]heptane, bicyclo [2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo [3.2.2]nonane, bicyclo [3.3.1]nonane, andbicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain amonocyclic cycloalkyl ring fused to either a phenyl, a monocycliccycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or amonocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl isattached to the parent molecular moiety through any carbon atomcontained within the monocyclic cycloalkyl ring. Cycloalkyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia. In certain embodiments, the fused bicyclic cycloalkyl is a5 or 6 membered monocyclic cycloalkyl ring fused to either a phenylring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 memberedmonocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a5 or 6 membered monocyclic heteroaryl, wherein the fused bicycliccycloalkyl is optionally substituted by one or two groups which areindependently oxo or thia. Multicyclic cycloalkyl ring systems are amonocyclic cycloalkyl ring (base ring) fused to either (i) one ringsystem selected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two other rings systems independentlyselected from the group consisting of a phenyl, a bicyclic aryl, amonocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl,a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclicheterocyclyl. The multicyclic cycloalkyl is attached to the parentmolecular moiety through any carbon atom contained within the base ring.In certain embodiments, multicyclic cycloalkyl ring systems are amonocyclic cycloalkyl ring (base ring) fused to either (i) one ringsystem selected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two other rings systems independentlyselected from the group consisting of a phenyl, a monocyclic heteroaryl,a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclicheterocyclyl. Examples of multicyclic cycloalkyl groups include, but arenot limited to tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl,and perhydrophenoxazin-1-yl.

“Cycloalkenyl” as used herein refers to a monocyclic, bicyclic, or amulticyclic cycloalkenyl ring system. Monocyclic ring systems are cyclichydrocarbon groups containing from 3 to 8 carbon atoms, where suchgroups are unsaturated (i.e., containing at least one annularcarbon-carbon double bond), but not aromatic. Examples of monocyclicring systems include cyclopentenyl and cyclohexenyl. Bicycliccycloalkenyl rings are bridged monocyclic rings or a fused bicyclicrings. Bridged monocyclic rings contain a monocyclic cycloalkenyl ringwhere two non-adjacent carbon atoms of the monocyclic ring are linked byan alkylene bridge of between one and three additional carbon atoms(i.e., a bridging group of the form —(CH₂)_(w)—, where w is 1, 2, or 3).Representative examples of bicyclic cycloalkenyls include, but are notlimited to, norbornenyl and bicyclo[2.2.2]oct-2-enyl. Fused bicycliccycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fusedto either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl,a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged orfused bicyclic cycloalkenyl is attached to the parent molecular moietythrough any carbon atom contained within the monocyclic cycloalkenylring. Cycloalkenyl groups are optionally substituted with one or twogroups which are independently oxo or thia. Multicyclic cycloalkenylrings contain a monocyclic cycloalkenyl ring (base ring) fused to either(i) one ring system selected from the group consisting of a bicyclicaryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicycliccycloalkenyl, and a bicyclic heterocyclyl; or (ii) two rings systemsindependently selected from the group consisting of a phenyl, a bicyclicaryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicycliccycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic orbicyclic heterocyclyl. The multicyclic cycloalkenyl is attached to theparent molecular moiety through any carbon atom contained within thebase ring. IN certain embodiments, multicyclic cycloalkenyl ringscontain a monocyclic cycloalkenyl ring (base ring) fused to either (i)one ring system selected from the group consisting of a bicyclic aryl, abicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, anda bicyclic heterocyclyl; or (ii) two rings systems independentlyselected from the group consisting of a phenyl, a monocyclic heteroaryl,a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclicheterocyclyl.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl,” as used herein, means a monocyclic, bicyclic, ora multicyclic heteroaryl ring system. The monocyclic heteroaryl can be a5 or 6 membered ring. The 5 membered ring consists of two double bondsand one, two, three or four nitrogen atoms and optionally one oxygen orsulfur atom. The 6 membered ring consists of three double bonds and one,two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl isconnected to the parent molecular moiety through any carbon atom or anynitrogen atom contained within the heteroaryl. Representative examplesof monocyclic heteroaryl include, but are not limited to, furyl,imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclicheteroaryl consists of a monocyclic heteroaryl fused to a phenyl, amonocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclicheterocyclyl, or a monocyclic heteroaryl. The fused cycloalkyl orheterocyclyl portion of the bicyclic heteroaryl group is optionallysubstituted with one or two groups which are independently oxo or thia.When the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl,or heterocyclyl ring, then the bicyclic heteroaryl group is connected tothe parent molecular moiety through any carbon or nitrogen atomcontained within the monocyclic heteroaryl portion of the bicyclic ringsystem. When the bicyclic heteroaryl is a monocyclic heteroaryl fused toa phenyl ring or a monocyclic heteroaryl, then the bicyclic heteroarylgroup is connected to the parent molecular moiety through any carbonatom or nitrogen atom within the bicyclic ring system. Representativeexamples of bicyclic heteroaryl include, but are not limited to,benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl,benzoxathiadiazolyl, benzothiazolyl, cinnolinyl,5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl,indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl,5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl,5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl,thienopyridinyl, 4,5,6,7-tetrahydrobenzo[c][1,2,5]oxadiazolyl, and6,7-dihydrobenzo[c][1,2,5]oxadiazol-4 (5H)-onyl. In certain embodiments,the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroarylring fused to either a phenyl ring, a 5 or 6 membered monocycliccycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 memberedmonocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl,wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia. The multicyclic heteroaryl group is a monocyclic heteroarylring (base ring) fused to either (i) one ring system selected from thegroup consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclicheterocyclyl, a bicyclic cycloalkenyl, and a bicyclic cycloalkyl; or(ii) two ring systems selected from the group consisting of a phenyl, abicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic orbicyclic heterocyclyl, a monocyclic or bicyclic cycloalkenyl, and amonocyclic or bicyclic cycloalkyl. The multicyclic heteroaryl group isconnected to the parent molecular moiety through any carbon atom ornitrogen atom contained within the base ring. In certain embodiments,multicyclic heteroaryl groups are a monocyclic heteroaryl ring (basering) fused to either (i) one ring system selected from the groupconsisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclicheterocyclyl, a bicyclic cycloalkenyl, and a bicyclic cycloalkyl; or(ii) two ring systems selected from the group consisting of a phenyl, amonocyclic heteroaryl, a monocyclic heterocyclyl, a monocycliccycloalkenyl, and a monocyclic cycloalkyl. Examples of multicyclicheteroaryls include, but are not limited to5H-[1,2,4]triazino[5,6-b]indol-5-yl,2,3,4,9-tetrahydro-1H-carbazol-9-yl, 9H-pyrido[3,4-b]indol-9-yl,9H-carbazol-9-yl, and acridin-9-yl.

The term “heteroarylalkyl” and “-alkylheteroaryl” as used herein, meansa heteroaryl, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofheteroarylalkyl include, but are not limited to, fur-3-ylmethyl,1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl, 1-(pyridin-4-yl)ethyl,pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrimidin-5-ylmethyl,2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl.

The term “heterocyclyl” as used herein, means a monocyclic, bicyclic, ormulticyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6 or 7membered ring containing at least one heteroatom independently selectedfrom the group consisting of O, N, and S where the ring is saturated orunsaturated, but not aromatic. The 3 or 4 membered ring contains 1heteroatom selected from the group consisting of O, N and S. The 5membered ring can contain zero or one double bond and one, two or threeheteroatoms selected from the group consisting of O, N and S. The 6 or 7membered ring contains zero, one or two double bonds and one, two orthree heteroatoms selected from the group consisting of O, N and S. Themonocyclic heterocycle is connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within themonocyclic heterocycle. Representative examples of monocyclicheterocycle include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl,thiadiazolidinyl, thiazolinyl, thiazolidinyl,thiomorpholinyl,1,1-dioxidothiomorpholinyl (thiomorpholine sulfone),thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclicheterocycle fused to either a phenyl, a monocyclic cycloalkyl, amonocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclicheteroaryl. The bicyclic heterocycle is connected to the parentmolecular moiety through any carbon atom or any nitrogen atom containedwithin the monocyclic heterocycle portion of the bicyclic ring system.Representative examples of bicyclic heterocyclyls include, but are notlimited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl,indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl,decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, andoctahydrobenzofuranyl. Heterocyclyl groups are optionally substitutedwith one or two groups which are independently oxo or thia. In certainembodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclicheterocyclyl ring fused to phenyl ring, a 5 or 6 membered monocycliccycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 memberedmonocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl,wherein the bicyclic heterocyclyl is optionally substituted by one ortwo groups which are independently oxo or thia. Multicyclic heterocyclylring systems are a monocyclic heterocyclyl ring (base ring) fused toeither (i) one ring system selected from the group consisting of abicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicycliccycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ringssystems independently selected from the group consisting of a phenyl, abicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic orbicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and amonocyclic or bicyclic heterocyclyl. The multicyclic heterocyclyl isattached to the parent molecular moiety through any carbon atom ornitrogen atom contained within the base ring. In certain embodiments,multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring(base ring) fused to either (i) one ring system selected from the groupconsisting of a bicyclic aryl, a bicyclic heteroaryl, a bicycliccycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or(ii) two other rings systems independently selected from the groupconsisting of a phenyl, a monocyclic heteroaryl, a monocycliccycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.Examples of multicyclic heterocyclyl groups include, but are not limitedto 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl,9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl,10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl,1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl,12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

The term “nitro” as used herein, means a —NO₂ group.

The term “oxo” as used herein means a ═O group.

The term “saturated” as used herein means the referenced chemicalstructure does not contain any multiple carbon-carbon bonds. Forexample, a saturated cycloalkyl group as defined herein includescyclohexyl, cyclopropyl, and the like.

The term “thia” as used herein means a ═S group.

The term “unsaturated” as used herein means the referenced chemicalstructure contains at least one multiple carbon-carbon bond, but is notaromatic. For example, a unsaturated cycloalkyl group as defined hereinincludes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.

As used herein, the phrase “pharmaceutically acceptable salt” refers toboth pharmaceutically acceptable acid and base addition salts andsolvates. Such pharmaceutically acceptable salts include salts of acidssuch as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic,formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric,tartaric, maleic, hydroiodic, alkanoic such as acetic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like. Non-toxicpharmaceutical base addition salts include salts of bases such assodium, potassium, calcium, ammonium, and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

EXAMPLES

Unless otherwise stated, all chemicals were purchased from commercialsuppliers and used without further purification. The microwaveirradiation was performed in a CEM Discover System. The final purity ofall compounds was determined by analytical LCMS with Phenomenex OnyxMonolithic C18 column (4.6 mm×100 mm). The products were detected by UVat 220 nm. All compounds were determined to be >95% pure by this method.The purification by preparative HPLC was performed on Waters Xterra PrepRP18 OBD 5 μM (19 mm×50 mm) with CH₃CN/H₂O and 0.1% TFA as eluent. Themass spectra were recorded with an Agilent Ion Trap Mass Spectrometer.NMR spectra were recorded on either a Bruker 500 MHz spectrometer or aBruker 300 MHz spectrometer at ambient temperature. Inhibitors weresynthesized through several different routes, as represented in Schemes1-3. Syntheses of compounds 2, 4, 7 and 9 have been previously reportedin Johnson et al., J. Med. Chem. 55, 2416-2426 (2012), incorporated byreference. All other syntheses and compound characterization data arepresented below.

General Procedure A (Examples 1, 12-23): A mixture of2-(methoxy(naphthalene-7-yl)methylene)malononitrile (50 mg, 0.21 mmol)prepared as previously reported and the appropriate alkyl hydrazine (1.2equiv) were dissolved in ethanol (1 ml) in an capped microwave tube. Thereaction mixture was microwave irradiated at 100° C. for 30min. Aftercooling down, 0.2 ml of saturated aqueous NaOH was added in situ and thesolution was microwave irradiated at 110° C. for 20min. After coolingdown to 0° C., concentrated HCl was added slowly to neutralize thesolution. The solution was extracted with ethyl acetate, washed withwater twice. The solvent was removed and the residue was dissolved inmethanol and purified by preparative HPLC with an acetonitrile/watergradient with 0.1% TFA to yield the final products. Using thisprocedure, only one regioisomer as indicated in the scheme was isolatedfrom the reaction.

General Procedure B (Examples 3, 24, 25, 27, 30, 34-39): A mixture ofthe appropriate aromatic aldehyde (1.5 mmole) and powdert-butylhydrazine HCl salt (1.1 equiv) with DIPEA (1.1 equiv) weredissolved in 3 ml of anhydrous DMF in a capped microwave tube. Themixture was microwave irradiated at 80° C. for 20 min or stirred at roomtemperature for 2h. After cooling down to 0° C., to the solution wasslowly added NBS (1.1 equiv) in 0.5 ml DMF. The mixture was kept at 0°C. and stirred for 2h. Cyanoacetamide anion was generated by treatmentof cyanoacetamide (1.1 equiv) in 3 ml of anhydrous ethanol with 2.5equiv of sodium ethoxide. This mixture was mixed with the abovebromohydrazone DMF solution. The reaction was stirred overnight at roomtemperature. After most solvents were removed, the residue was dilutedwith ethyl acetate and washed with water, brine, dried over Na₂SO₄ andconcentrated under reduced pressure. Purification via flashchromatography on silica gel eluted with MeOH—DCM and further withpreparative HPLC gave the HPLC pure final products.

General Procedure C (Examples 6, 8, 10, 11): 1, 3 and 25 were treatedwith 1 ml of concentrated sulfuric acid respectively for 1h at roomtemperature. After cooling down to 0° C., solid NaOH was added in smallportions until the solution became neutral or basic. The slurry mixturewas slowly diluted with water and extracted with ethyl acetate twice.The organic extract was washed with water, brine, dried over Na₂SO₄ andconcentrated under reduced pressure to give intermediate A.4-Methylsulfonyloxypiperidine(0.8mmol) and A (0.08mmol) in 1 ml of DMFcontaining K₂CO₃ (1.0mmol) was microwave irradiated at 90° C. for 30min. After solvent was removed, the residues were extracted with ethylacetate, washed with water, brine, dried over Na₂SO₄ and concentratedunder reduced pressure. The mixture was Boc deprotected if necessarybefore HPLC purification. The preparative HPLC purification can separatethe isomers in N-1 and N-2 positions and the N-1 position product wascollected and confirmed by ¹H NMR in d6-DMSO.

Example 1 Compound 1, also 1439

1:5-amino-1-tert-butyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide wassynthesized using t-butyl hydrazine following General Procedure A. ¹HNMR (500 MHz, CDCl₃) δ 8.05 (1H, s), 7.92 (1H, d, J 8.6), 7.88 (2H, dd,J 8.7, 4.6), 7.65 (1H, d, J 1.8), 7.56-7.48 (2H, m), 5.72 (2H, s), 1.70(9H, s). MS (ESI) (M+H)³⁰ =309.6.

Comparative Example 2 Compound 2

2:1-tert-butyl-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amineExample 3 Compound 3, also 1473

3:5-amino-1-tert-butyl-3-(6-ethoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamidewas synthesized using 6-ethoxynaphthalene-2-carboxalde hydefollowingGeneral Procedure B. ¹H NMR (500 MHz, CDCl₃) δ 7.94 (1H, s), 7.78 (2H,dd, J 12.5, 8.7), 7.58 (1H, dd, J 8.0, 1.1), 7.18 (1H, dd, J8.8, 2.5),7.14 (1H, d, J2.4), 5.41 (2H, s), 4.23-4.11 (2H, m), 1.69 (9H, s), 1.49(3H, t, J 5.8). MS (ESI) (M+H)³⁰ =353.6.

Comparative Example 4 Compound 4, also 1281

4:1-tert-butyl-3-(6-ethoxynaphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amineExample 5 Compound 5, also 1503

Intermediate B: To a stirred suspension of 1H3-amino-1H-pyrazole-4-carbonitrile (1.08 g, 10 mmol) in concentrated HCl(13.0 ml) was added a solution of sodium nitrite (1.38 g, 20 mmol) inwater (3.0 ml) over 5 min at 0° C. To the resulting reaction mixture wasadded a solution of KI (4.1 g, 25 mmol) in water (7.0 ml) over 10 min.The reaction mixture was stirred for 5 min further, then extracted withether (3×30 ml) and the combined organic extracts were washed withNa₂S₂O₃ (2×30ml), dried over Na₂SO₄ and concentrated under reducedpressure to give 1.63 g of B as light yellow solid, yield: 74.6%. MS(ESI) (M+H)⁺=220.9.

Intermediate C: To a solution of B (110 mg, 0.5 mmol) in tert-butanol (5ml) was added sulfuric acid (0.110 ml). The reaction mixture was heatedat 100° C. for 3 h. After cooling down to 0° C., solid NaOH was added insmall portions until the solution became neutral or basic. The slurrymixture was slowly diluted with water and extracted with ethyl acetatetwice. The organic extract was washed with water, brine, dried overNa₂SO₄ and concentrated under reduced pressure. Purification via flashchromatography on silica gel gave 50 mg of intermediate C as a whitesolid, yield: 34.1%. MS (ESI) (M+H)⁺=294.8.

1-tert-butyl-3-(6-ethoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide (5):To a solution of C (20 mg, 0.068 mmol) in a mixture of DME:H₂O=3:1 (4ml) was added K₂CO₃ (28 mg, 0.2 mmol), Pd(PPh₃)₄ (8 mg, 0.007 mmol) and(6-ethoxynaphthalen-2yl)boronic acid (16 mg, 0.075 mmol). The mixturewas microwave irradiated at 85° C. for 20 min. After cooling down toroom temperature, ethyl acetate was added and organic layer was washedwith water, brine, dried over Na₂SO₄ and concentrated under reducedpressure. Purification via flash chromatography on silica gel elutedwith MeOH—DCM and further with preparative HPLC gave the HPLC pure finalproduct,1-tert-butyl-3-(6-ethoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide. ¹HNMR (300 MHz, DMSO) δ 8.36 (1H, s), 8.23 (1H, s), 7.81 (3H, m), 7.42(1H, s), 7.32 (1H, s), 7.16 (1H, d, J 8.9), 7.01 (1H, s), 4.17 (2H, q, J7.1), 1.60 (9H, s), 1.42 (3H, t, J6.9). MS (ESI) (M+H)⁺=338.8.

Example 6 Compound 6, also 1447

6:5-amino-3-(naphthalen-2-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazole-4-carboxamidewas synthesized using 1-Boc-4-Methanesulfonyloxymethyl-piperidine and 1which was pre-treated with sulfuric acid following General Procedure Cor using 4-(hydrazinylmethyl)-piperidine following General Procedure A.¹H NMR (500 MHz, MeOD) δ 8.19 (1H, s), 8.04 (1H, d, J 8.4), 7.95 (2H,m), 7.65 (1H, d, J 8.4), 7.62-7.54 (2H, m), 4.13 (2H, d, J 7.0), 3.41(2H, d, J 13.6), 2.99 (2H, m), 2.30 (1H, s), 1.92 (2H, d, J 12.6), 1.63(2H, m). MS (ESI) (M+H)⁻=350.5.

Comparative Example 7 Compound 7, also 1291

7:3-(naphthalen-2-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Example 8 Compound 8, also 1516

8:5-amino-3-(6-ethoxynaphthalen-2-yl)-1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazole-4-carboxamidewas synthesized using 1-methyl-4-methanesulfonyloxymethylpiperidine and3, which was pre-treated with sulfuric acid following General ProcedureC. ¹H NMR (500 MHz, MeOD) δ 8.09 (1H, d, J 7.4), 7.93 (1H, d, J 8.6),7.86 (1H, dd, J 8.4, 3.9), 7.60 (1H, d, J 8.6), 7.30 (1H, d, J2.0), 7.21(1H, dd, J 8.6, 2.0), 4.27-4.10 (4H, m), 3.71 (2H, m), 3.06 (2H, m),2.99-2.86 (3H, m), 2.83 (1H, m), 2.26 (1H, m), 1.99 (2H, m), 1.72 (1H,m), 1.44 (3H, t, J 7.0). MS (ESI) (M+H)⁺=408.6.

Comparative Example 9 Compound 9, also 1294

9:3-(6-ethoxynaphthalen-2-yl)-1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.Example 10 Compound 10, also 1501

10:5-amino-3-(6-methoxynaphthalen-2-yl)-1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazole-4-carboxamidewas synthesized using compound 11 and1-methyl-4-Methanesulfonyloxymethylpiperidine following GeneralProcedure C. ¹H NMR (500 MHz, MeOD) δ 8.11 (1H, s), 7.95 (1H, d, J 8.5),7.87 (1H, m), 7.61 (1H, d, J 8.5), 7.32 (1H, d, J 2.2), 7.22 (1H, m),4.20 (2H, m), 3.91 (3H, s), 3.73-3.60 (1H, m), 3.54 (1H, m), 3.19 (1H,m), 3.13-2.99 (1H, m), 2.91 (3H, s), 2.41 (1H, m), 2.28 (1H, m), 2.05(2H, m), 1.74 (1H, m). MS (ESI) (M+H)⁺=394.5.

Example 11 Compound 11, also 1504

11:5-amino-3-(6-methoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide wassynthesized from 25 following General Procedure C as one of theintermediate A. ¹H NMR (500 MHz, MeOD) δ 7.96 (1H, s), 7.90 (1H, d, J8.5), 7.83 (1H, d, J 9.0), 7.56 (1H, m), 7.30 (1H, t, J 3.7), 7.20 (1H,m), 3.30 (3H, s). MS (ESI) (M+H)⁺=283.6.

Example 12 Compound 12, also 1491

12:5-amino-1-ethyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide wassynthesized using ethyl hydrazine following General Procedure A. ¹H NMR(500 MHz, CDCl₃) δ 8.06 (1H, d, J 1.2), 7.93 (1H, d, J 8.4), 7.88 (2H,dd, J 6.0, 3.4), 7.66 (1H, dd, J 8.4, 1.6), 7.57-7.48 (2H, m), 5.44 (2H,s), 4.01 (2H, q, J 7.3), 1.46 (3H, t, J 7.3). MS (ESI) (M+H)⁺=281.8.

Example 13 Compound 13, also 1492

13:5-amino-1-isopropyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide wassynthesized using isopropylhydrazine following General Procedure A. ¹HNMR (500 MHz, CDCl₃) δ 8.05 (1H, s), 7.93 (1H, d, J 8.5), 7.88 (2H, dd,J 8.5, 5.2), 7.66 (1H, d, J 3.4), 7.56-7.48 (2H, m), 5.45 (2H, s), 5.30(2H, s), 4.35-4.22 (1H, m), 1.53 (6H, d, J 6.6). MS (ESI) (M+H)⁺=295.7.

Example 14 Compound 14, also 1493

14:5-amino-1-isobutyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide wassynthesized using isobutylhydrazine following General Procedure A. ¹HNMR (500 MHz, CDCl₃) δ 8.05 (1H, s), 7.93 (1H, d, J 8.4), 7.90-7.83 (2H,m), 7.65 (1H, dd, J 8.4, 1.7), 7.57-7.48 (2H, m), 5.45 (2H, s), 5.32(2H, s), 3.75 (2H, d, J 7.4), 2.38-2.23 (1H, m), 0.98 (6H, m). MS (ESI)(M+H)⁺=309.7.

Example 15 Compound 15, also 1495

15:5-amino-1-(cyclopropylmethyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamidewas synthesized using cyclopropylmethylhydrazine following GeneralProcedure A. ¹H NMR (500 MHz, CDCl₃) δ 8.06 (1H, s), 7.94 (1H, d, J8.3), 7.91-7.86 (2H, m), 7.66 (1H, dd, J 8.4, 1.7), 7.56-7.51 (2H, m),5.48 (2H, s), 3.91 (2H, d, J 6.6), 1.36-1.23 (1H, m), 0.66 (2H, m),0.47-0.40 (2H, m). MS (ESI) (M+H)⁺=307.8.

Example 16 Compound 16, also 1496

16:5-amino-1-(cyclohexylmethyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamidewas synthesized using 1-(cyclohexylmethyl)hydrazine following GeneralProcedure A. ¹H NMR (500 MHz, CDCl₃) δ 8.04 (1H, s), 7.98-7.82 (3H, m),7.64 (1H, m), 7.59-7.47 (2H, m), 3.77 (2H, d, J 7.3), 2.09-1.90 (1H, m),1.72 (5H, m), 1.23 (3H, m), 1.03 (2H, m). MS (ESI) (M+H)⁻=349.7.

Example 17 Compound 17, also 1497

17:5-amino-1-cyclohexyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamidewas synthesized using cyclohexylhydrazine following General Procedure A.¹H NMR (500 MHz, CDCl₃) δ 8.03 (1H, s), 7.95 (1H, d, J 8.4), 7.93-7.83(2H, m), 7.64-7.51 (3H, m), 3.91-3.77 (1H, m), 2.08-1.89 (6H, m), 1.73(1H, m), 1.41 (2H, m), 1.27 (1H, m). MS (ESI) (M+H)⁺=335.7.

Example 18 Compound 18, also 1499

18:5-amino-3-(naphthalen-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamidewas synthesized using 2,2,2-trifluoromethylhydrazine following GeneralProcedure A except using different hydrolytic condition. Hydrolysis ofcyano group to amide was performed by using 30% H₂O₂ (0.2 ml), NH₄OH(0.6 ml) and ethanol (0.6 ml) at room temperature for 5 days. ¹H NMR(500 MHz, CDCl₃) δ 8.06 (1H, s), 7.95 (1H, d, J 8.3), 7.89 (2H, m), 7.64(1H, m), 7.60-7.50 (2H, m), 5.57 (4H, broad), 4.62 (2H, m). MS (ESI)(M+H)⁺=335.7.

Example 19 Compound 19, also 1502

19:5-amino-3-(naphthalen-2-yl)-1-neopentyl-1H-pyrazole-4-carboxamide wassynthesized using neopentylhydrazine following General Procedure A. ¹HNMR (500 MHz, CDCl₃) δ 8.13 (1H, s), 7.99 (1H, s), 7.92 (2H, s),7.70-7.64 (1H, m), 7.59 (2H, s), 3.99 (2H, d, J 12.1), 1.14 (9H, s). MS(ESI) (M+H)⁺=323.8.

Example 20 Compound 20, also 1498

20:5-amino-1-(1-methylpiperidin-4-yl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamidewas synthesized using 1-(1-methylpiperidin-4-yl)hydrazine followingGeneral Procedure A. ¹H NMR (500 MHz, MeOD) δ 8.04 (1H, s), 7.99 (1H, d,J 8.6), 7.93 (2H, m), 7.60 (1H, dd, J 7.5, 1.5), 7.55 (2H, d, J 8.3),4.60-4.49 (1H, m), 3.68 (2H, m), 3.27-3.21 (2H, m), 2.94 (3H, s), 2.39(2H, m), 2.24 (2H, m). MS (ESI) (M+H)⁺=350.6.

Example 21 Compound 21, also 1500

21:5-amino-1-((1-methylpiperidin-4-yl)methyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamidewas synthesized using 1-methyl-4-(hydrazinylmethyl)piperidine followingGeneral Procedure A or General Procedure C by using 1 and1-methyl-4-methanesulfonyloxymethylpiperidine. ¹H NMR (500 MHz, MeOD) δ8.18 (1H, s), 8.05 (1H, d, J 8.6), 8.00-7.91 (2H, m), 7.65 (1H, d, J8.9), 7.62-7.54 (2H, m), 4.12 (2H, d, J 7.0), 3.53 (2H, d, J 13.1), 3.02(2H, t, J 12.0), 2.83 (3H, s), 2.28 (1H, m), 1.97 (2H, d, J 12.1), 1.71(2H, m). MS (ESI) (M+H)⁺=364.6.

Example 22 Compound 22, also 1518

22:5-amino-1-(2-hydroxyethyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamidewas synthesized using 2-hydrazinylethanol following General Procedure A.¹H NMR (500 MHz, MeOD) δ 8.04 (1H, s), 7.96 (1H, d, J 8.5), 7.93-7.86(2H, m), 7.60 (1H, m), 7.52 (2H, m), 4.09 (2H, t, J 5.3), 3.88 (2H, t, J5.2). MS (ESI) (M+H)⁺=297.5.

Example 23 Compound 23, also 1519

23:5-amino-1-(2-morpholinoethyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamidewas synthesized using 4-(2-hydrazinoethyl)morpholine following GeneralProcedure A. ¹H NMR (500 MHz, DMSO) δ 8.07 (1H, s), 8.04-7.91 (3H, m),7.64 (1H, m), 7.56 (2H, dd, J 6.2, 3.3), 4.50 (2H, t, J 6.8), 3.97 (2H,m), 3.80 (2H, m), 3.55 (2H, t, J 6.7), 3.48 (2H, m), 3.17 (2H, m). MS(ESI) (M+H)⁻=366.6.

Example 24 Compound 24, also 1457

24:5-amino-1-(tert-butyl)-3-(6-hydroxynaphthalen-2-yl)-1H-pyrazole-4-carboxamidewas synthesized using 6-hydroxynaphthalene-2-carbaldehyde followingGeneral Procedure B. ¹H NMR (500 MHz, CDCl₃) δ 7.89 (1H, s), 7.71 (2H,d, J 8.1), 7.50 (1H, m), 7.12-7.07 (2H, m), 5.72 (2H, s), 1.71 (28H, s).MS (ESI) (M+H)⁺=325.6.

Example 25 Compound 25, also 1458

25:5-amino-1-(tert-butyl)-3-(6-methoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamidewas synthesized using 6-methoxynaphthalene-2-carbaldehyde followingGeneral Procedure B. ¹H NMR (500 MHz, CDCl₃) δ 7.96 (1H, s), 7.79 (2H,m), 7.60 (1H, m), 7.18 (2H, m), 3.94 (3H, s), 1.69 (9H, s). MS (ESI)(M+H)⁺=340.0.

Example 26 Compound 26, also 1474

26:5-amino-1-(tert-butyl)-3-(6-propoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide

To a solution of 24 (20 mg) in DMF(0.5 ml) was added K₂CO₃ (20 equiv),1-bromopropane (20 equiv). The mixture was microwave irradiated at 75°C. for 40 min. After cooling down to room temperature, ethyl acetate wasadded and the organic layer was washed with water, brine, dried overNa₂SO₄ and concentrated under reduced pressure. Purification viapreparative HPLC gave the HPLC pure final product. ¹H NMR (500 MHz,CDCl₃) δ 7.97 (1H, s), 7.80 (2H, d, J 13.3), 7.57 (1H, s), 7.20 (1H, d,J 7.2), 7.15 (1H, s), 4.05 (2H, t, J 6.3), 1.88 (2H, m), 1.78 (9H, s),1.09 (3H, t, J7.4). MS (ESI) (M+H)⁺=367.6.

Example 27 Compound 27, also 1480

27:5-amino-1-(tert-butyl)-3-(2-methylbenzofuran-3-yl)-1H-pyrazole-4-carboxamidewas synthesized using 2-methylbenzofuran-3-carbaldehyde followingGeneral Procedure B. ¹H NMR (500 MHz, CDCl₃) δ 7.46 (1H, d, J8.1), 7.40(1H, d, J7.3), 7.28 (1H, t, J7.1), 7.23 (1H, t, J7.0), 2.50 (3H, s),1.70 (9H, s). MS (ESI) (M+H)⁺=313.7.

Examples 28 and 29 Compound 28 (also 1459)and 29(also 1460)

General Procedure D(28, 29):

Intermediate D was synthesized using 2-fluoro-4-formylbenzonitrilefollowing General Procedure B. H¹NMR (500 MHz, MeOD) δ 7.81 (1H, t, J7.3), 7.59 (2H, t, J9.7), 1.67 (9H, s). MS (ESI) (M+H)⁻=302.7.

A solution of D (20 mg) in ethanol(0.5 ml) and hydrazine monohydrate ormethylhydrazine (60 μl) was microwave irradiated at 120° C. for 40 min.After cooling down to room temperature, ethyl acetate was added and theorganic layer was washed with water three times, brine, dried overNa₂SO₄ and concentrated under reduced pressure. Purification viapreparative HPLC gave the HPLC pure final product.

28:3-(3-amino-1H-indazol-6-yl)-1-(tert-butyl)-1H-pyrazole-4-carboxamidewas synthesized using hydrazine monohydrate following General ProcedureD. ¹H NMR (500 MHz, DMSO) δ 7.72 (1H, d, J 8.2), 7.26 (1H, s), 6.98 (1H,d, J 8.2), 6.29 (2H, s), 5.39 (2H, s), 1.55 (9H, s). MS (ESI)(M+H)⁻=314.6.

29:3-(3-amino-1-methyl-1H-indazol-6-yl)-1-(tert-butyl)-1H-pyrazole-4-carboxamidewas synthesized using methylhydrazine following General Procedure D. ¹HNMR (500 MHz, DMSO) δ 7.71 (1H, d, J 8.2), 7.36 (1H, s), 6.94 (1H, d, J8.2), 6.32 (2H, s), 5.46 (2H, s), 3.72 (3H, s), 1.56 (9H, s). MS (ESI)(M+H)⁺=328.6.

Example 30 Compound 30, also 1472

30:5-amino-1-(tert-butyl)-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxamidewas synthesized using 1-methyl-1H-indazole-5-carbaldehyde followingGeneral Procedure B. B. ¹H NMR (500 MHz, DMSO) δ8.72 (1H, s), 7.57 (1H,d, J 8.3), 7.45 (1H, s), 7.39 (1H, d, J6.9), 3.65 (3H, s), 1.58 (9H, s).MS (ESI) (M+H)⁺=313.8.

Example 31 Compound 31, also 1482

Intermediate E was synthesized using 3-nitro-4-fluorobenzaldehydefollowing General Procedure B except using malononitrile instead ofcyanoactamide. ¹H NMR (500 MHz, CDCl₃) δ 8.59 (1H, m), 8.21-8.13 (1H,m), 7.37-7.27 (1H, m), 1.69 (9H, s). MS (ESI) (M+H)⁻=304.8.

Intermediate F: A solution of E (160 mg, 0.53 mmol) in ethanol (1.0 ml)and methylamine (4 ml, 33% wt in EtOH) was stirred at room temperaturefor 30 min. After solvents were removed, the residue was diluted withethyl acetate. The organic extract was washed with water, brine, driedover Na₂SO₄ and concentrated under reduced pressure. The residue wasdissolved in 5 ml of methanol. To the solution, ammonium formate (5equiv) was added with stirring, then powder Zn (5 equiv) was addedslowly with strong stirring. After 10 min, the solvent was removed and20 ml of ethyl acetate was added. The organic extract was purified viaflash chromatography on silica gel to obtain 96 mg of F in brownishsolid. ¹H NMR (500 MHz, MeOD) δ 7.32-7.18 (2H, m), 6.60 (1H, d, J 8.2),2.86 (3H, s), 1.64 (9H, s). MS (ESI) (M+H)=285.6.

31:5-amino-1-(tert-butyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-pyrazole-4-carboxamide. A solution of F (12 mg) inanhydrous THF (1.0 ml) was added 1,1′-carbonyldiimidazole (2.5 equiv).The mixture was microwave irradiated at 70° C. for 30 min. After coolingdown to room temperature, ethyl acetate was added and the organic layerwas washed with water, brine, dried over Na₂SO₄ and concentrated underreduced pressure. The residue was dissolved in 1 ml of ethanol, 0.2 mlof saturated aqueous NaOH was added and the solution was microwaveirradiated at 110° C. for 20min. After cooling down to 0° C.,concentrated HCl was added slowly to neutralize the solution. Thesolution was extracted with ethyl acetate, washed with water twice. Thesolvent was removed and the residue was dissolved in methanol andpurified by preparative HPLC with an acetonitrile/water gradient with0.1% TFA to yield the final product. ¹H NMR (500 MHz, DMSO) δ 10.94 (1H,s), 7.15 (2H, m), 7.05 (1H, s), 2.53 (3H, s), 1.59 (9H, s). MS (ESI)(M+H)⁺=329.5.

Example 32 Example 32, also 1487

32:5-amino-1-(tert-butyl)-3-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazole-4-carboxamide. To a solution of F (12 mg)in THF(1.0 ml) was added acetaldehyde (6 equiv) and sodium bisulfite (6equiv). The mixture was microwave irradiated at 70° C. for 15 min. Aftercooling down to room temperature, ethyl acetate was added and theorganic layer was washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure. The residue was dissolved in 1 ml of ethanol,0.2 ml of saturated aqueous NaOH was added and the solution wasmicrowave irradiated at 110° C. for 20min. After cooling down to 0° C.,concentrated HCl was added slowly to neutralize the solution. Thesolution was extracted with ethyl acetate, washed with water twice. Thesolvent was removed and the residue was dissolved in methanol andpurified by preparative HPLC with an acetonitrile/water gradient with0.1% TFA to yield the final product. H¹NMR (500 MHz, CDCl₃) δ 8.22 (1H,s), 7.81 (1H, dd, J 8.4, 1.5), 7.27 (1H, d, J 8.4), 4.45 (2H, s), 3.71(3H, s),2.61 (3H, s), 1.67(9H, s). MS (ESI) (M+H)⁺=327.7.

Example 33 Compound 33, also 1488

33:5-amino-3-(2-amino-1-methyl-1H-benzo[d]imidazol-5-yl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide.To a solution of F (12 mg) in anhydrous ethanol(0.5 ml) was added BrCN(2.5 equiv). The mixture was stirred at room temperature overnight.Ethyl acetate was added and washed with saturated NaHCO₃, brine, driedover Na₂SO₄ and concentrated under reduced pressure. The residue wasdissolved in 1 ml of ethanol, 0.2 ml of saturated aqueous NaOH was addedand the solution was microwave irradiated at 110° C. for 20min. Aftercooling down to 0° C., concentrated HCl was added slowly to neutralizethe solution. The solution was extracted with ethyl acetate, washed withwater twice. The solvent was removed and the residue was dissolved inmethanol and purified by preparative HPLC with an acetonitrile/watergradient with 0.1% TFA to yield the final product. H¹NMR (500 MHz, MeOD)δ 7.67-7.60 (2H, m), 7.55 (1H, d, J 7.2), 3.72 (3H, s), 3.32 (2H, s),1.72 (9H, s). MS (ESI) (M+H)⁺=328.6.

Example 34 Compound 34, also 1489

34:5-amino-1-(tert-butyl)-3-(2-oxo-2H-chromen-6-yl)-1H-pyrazole-4-carboxamidewas synthesized using coumarin-6-carbaldehyde following GeneralProcedure B. ¹H NMR (500 MHz, CDCl₃) δ 7.73 (3H, m), 7.41 (1H, d, J8.5), 6.48 (1H, d, J 9.5), 5.70 (2H, s), 5.13 (2H, s), 1.68 (9H, s). MS(ESI) (M+H)⁻=327.7.

Example 35 Compound 35, also 1455

35:5-amino-1-(tert-butyl)-3-(quinolin-2-yl)-1H-pyrazole-4-carboxamidewas synthesized using quinoline-2-carbaldehyde following GeneralProcedure B. ¹H NMR (500 MHz, CDCl₃) δ 8.39 (1H, d, J 8.8), 8.17 (1H, d,J8.9), 7.95 (1H, d, J 8.4), 7.82 (1H, d, J6.9), 7.74-7.66 (1H, m),7.57-7.50 (1H, m), 6.08 (2H, s), 1.73 (9H, s). MS (ESI) (M+H)⁺=310.6.

Example 36 Compound 36, also 1481

36:5-amino-1-(tert-butyl)-3-(6-ethoxyquinolin-2-yl)-1H-pyrazole-4-carboxamidewas synthesized using 6-ethoxyquinoline-2-carbaldehyde following GeneralProcedure B. ¹H NMR (500 MHz, CDCl₃) δ 8.33 (1H, d, J 8.8), 8.05 (1H, d,J 8.9), 7.84 (1H, d, J 9.1), 7.34 (1H, dd, J 9.1, 2.7), 7.08 (1H, d, J2.7), 6.04 (2H, s), 4.17 (2H, m), 1.72 (9H, s), 1.50 (3H, t, J 7.0). MS(ESI) (M+H)⁺=354.6.

Example 37 Compound 37, also 1471

37:5-amino-1-(tert-butyl)-3-(quinolin-6-yl)-1H-pyrazole-4-carboxamidewas synthesized using quinoline-6-carbaldehyde following GeneralProcedure B. ¹H NMR (500 MHz, CDCl₃) δ 8.95 (1H, d, J 4.5), 8.18 (2H,m), 8.05 (1H, s), 7.91 (1H, d, J 5.6), 7.50-7.40 (1H, m), 5.73 (2H, s),1.68 (9H, s). MS (ESI) (M+H)⁺=310.8.

Example 38 Compound 38, also 1456

38:5-amino-1-(tert-butyl)-3-(quinolin-3-yl)-1H-pyrazole-4-carboxamidewas synthesized using quinoline-3-carbaldehyde prepared according to theliterature procedure following General Procedure B. ¹H NMR (500 MHz,DMSO) δ 9.01 (1H, s), 8.44 (1H, s), 8.06 (2H, d, J 9.0), 7.84-7.74 (1H,m), 7.68-7.60 (1H, m), 6.23 (2H, s), 1.61 (9H, s). MS (ESI)(M+H)⁺=310.7.

Example 39 Compound 39, also 1517

39:5-amino-1-(tert-butyl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamidewas synthesized using 7-ethoxyquinoline-3-carbaldehyde preparedaccording to the literature procedure following General Procedure B. ¹HNMR (500 MHz, CDCl₃) δ 9.19 (1H, s), 8.84 (1H, s), 7.98 (1H, d, J 13.2),7.77 (1H, s), 7.47 (1H, d, J 10.5), 6.10 (2H, s), 4.28 (2H, m), 1.68(9H, s), 1.53 (3H, t, J 6.9). MS (ESI) (M+H)⁺=354.5.

Example 40 Compound 1572

1572:5-amino-3-(7-ethoxyquinolin-3-yl)-1-isopropyl-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, CDCl₃) δ 9.08 (s, 1H), 8.44 (s, 1H), 7.81 (d, J=9.0 Hz,1H), 7.53 (s, 1H), 7.31 (d, J=9.0 Hz, 1H), 5.45 (s, 2H), 5.21 (s, 2H),4.39-4.30 (m, 1H), 4.26 (q, J=6.9 Hz, 2H), 1.64-1.49 (m, 9H); MS (ESI)(M+H)⁺=340.5 ; HPLC analysis: 97.9% purity.

Example 41 Compound 1573

1573:5-amino-3-(7-ethoxyquinolin-3-yl)-1-isobutyl-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, CDCl₃) δ 9.05 (s, 1H), 8.37 (s, 1H), 7.79 (d, J=8.8 Hz,1H), 7.53 (s, 1H), 7.30 (d, J=8.8 Hz, 1H), 4.25 (q, J=6.8 Hz, 2H), 3.78(d, J=7.4 Hz, 2H), 2.39-2.25 (m, 1H), 1.54 (t, J=6.9 Hz, 3H), 1.03 (d,J=6.6 Hz, 6H); MS (ESI) (M+H)⁺=354.6 ; HPLC analysis: 96.9% purity.

Example 42 Compound 1591

1591:5-amino-3-(7-ethoxyquinolin-3-yl)-1-neopentyl-1H-pyrazole-4-carboxamide.¹H NMR (300 MHz, CDCl₃) δ 9.06 (d, J=2.4 Hz, 1H), 8.39 (s, 1H), 7.80 (d,J=9.0 Hz, 1H), 7.57 (s, 1H), 7.31 (dd, J₁=9.0, 2.4 Hz, 1H), 5.48 (s,2H), 5.21 (s, 2H), 4.25 (q, J=7.0 Hz, 2H), 3.77 (s, 2H), 1.54 (t, J=7.0Hz, 3H), 1.10 (s, 9H); MS (ESI) (M+H)⁺=368.6 ; HPLC analysis: 95.0%purity.

Example 43 Compound 1575

1575:5-amino-3-(7-ethoxyquinolin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, CDCl₃) δ 9.03 (s, 1H), 8.32 (s, 1H), 7.78 (d, J=9.0 Hz,1H), 7.47 (s, 1H), 7.29 (dd, J=9.0, 2.2 Hz, 1H), 5.65 (s, 2H), 5.23 (s,2H), 4.65 (t, J=6.9 Hz, 2H), 4.24 (q, J=6.9 Hz, 2H), 1.54 (t, J=6.9 Hz,3H); MS (ESI) (M+H)⁺=380.5; HPLC analysis: 96.8% purity.

Example 44 Compound 1598

1598:5-amino-1-(cyclopropylmethyl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, CDCl₃) δ 9.06 (s, 1H), 8.37 (s, 1H), 7.79 (d, J=9.0 Hz,1H), 7.52 (s, 1H), 7.30 (dd, J=9.0, 2.3 Hz, 1H), 5.50 (s, 2H), 5.24 (s,2H), 4.24 (q, J=6.9 Hz, 2H), 3.93 (d, J=6.6 Hz, 2H), 1.53 (t, J=7.0 Hz,3H), 1.31 (m, 1H), 0.69 (m, 2H), 0.46 (m, 2H); MS (ESI) (M+H)⁺=352.6;HPLC analysis: 99.0% purity.

Example 45 Compound 1652

1652:1-isobutyl-3-(2-(2,2,2-trifluoroethoxy)quinolin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.¹H NMR (500 MHz, MeOD) δ 9.32 (s, 1H), 9.27 (s, 1H), 8.29 (d, J=8.5 Hz,1H), 7.61 (d, J=8.5 Hz, 1H), 7.54 (s, 1H), 4.38 (q, J=6.2 Hz, 2H), 2.71(m, 2H), 2.46 (m, 2H), 1.92 (m, 2H), 1.56 (t, J=6.2 Hz, 3H); MS (ESI)(M+H)⁺=352.4 ; HPLC analysis: 98.7% purity.

Example 46 Compound 1605

1605:5-amino-1-cyclopentyl-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 9.28 (s, 1H), 9.24 (s, 1H), 8.29 (d, J=9.2 Hz,1H), 7.61 (dd, J=9.2, 2.1 Hz, 1H), 7.51 (s, 1H), 4.76-4.64 (m, 1H),4.45-4.32 (q, J=7.0 Hz, 2H), 2.23-2.06 (m, 4H), 2.03-1.90 (m, 2H),1.85-1.70 (m, 2H), 1.57 (t, J=7.0 Hz, 3H); MS (ESI) (M+H)⁺=366.3; HPLCanalysis: 95.0% purity.

Example 47 Compound 1571

1571:5-amino-1-cyclohexyl-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, CDCl₃) δ 9.05 (s, 1H), 8.35 (s, 1H), 7.78 (d, J=9.0 Hz,1H), 7.52 (s, 1H), 7.28 (dd, J=9.0, 2.3 Hz, 1H), 5.47 (s, 2H), 5.20 (s,2H), 4.24 (q, J=6.9 Hz, 2H), 3.96-3.82 (m, 1H), 2.10-1.92 (m, 6H), 1.53(t, J=6.9 Hz, 3H), 1.49-1.38 (m, 2H), 1.37-1.23 (m, 2H); MS (ESI)(M+H)⁺=380.5; HPLC analysis: 96.8% purity.

Example 48 Compound 1606

1606:5-amino-3-(7-ethoxyquinolin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, DMSO) δ 9.21 (s, 1H), 9.06 (s, 1H), 8.30 (d, J=9.1 Hz,1H), 7.65 (s, 1H), 7.56 (dd, J=9.1, 1.9 Hz, 1H), 4.51-4.43 (m, 1H), 4.29(q, J=6.9 Hz, 2H), 4.03-3.96 (m, 2H), 2.10-1.97 (m, 2H), 1.86-1.78 (m,2H), 1.46 (t, J=6.8 Hz, 3H); MS (ESI) (M+H)⁺=382.4; HPLC analysis: 99.5%purity.

Example 49 Compound 1604

1604:5-amino-1-cycloheptyl-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, CDCl₃) δ 9.03 (s, 1H), 8.31 (s, 1H), 7.76 (d, J=8.9 Hz,1H), 7.48 (s, 1H), 7.26 (dd, J=8.9, 1.8 Hz, 1H), 5.47 (s, 2H), 5.23 (s,2H), 4.23 (q, J=6.9 Hz, 2H), 4.14-4.02 (m, 1H), 2.21-2.03 (m, 4H),1.94-1.83 (m, 2H), 1.74-1.61 (m, 4H), 1.60-1.48 (m, 5H); MS (ESI)(M+H)⁺=394.6; HPLC analysis: 99.3% purity.

Example 50 Compound 1574

1574:5-amino-1-(cyclohexylmethyl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, CDCl₃) δ 9.04 (s, 1H), 8.31 (d, J=1.8 Hz, 1H), 7.77 (d,J=9.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.26 (dd, J=9.0, 2.0 Hz, 1H),5.44 (s, 2H), 5.18 (s, 2H), 4.24 (q, J=7.0 Hz, 2H), 3.80 (d, J=7.3 Hz,2H), 2.06-1.94 (m, 1H), 1.82-1.67 (m, 6H), 1.53 (t, J=7.0 Hz, 3H),1.32-1.24 (m, 2H), 1.014-1.01 (m, 2H) ; MS (ESI) (M+H)⁺=394.6; HPLCanalysis: 97.2% purity.

Example 51 Compound 1627

1627:5-amino-3-(7-ethoxyquinolin-3-yl)-1-(1-hydroxypropan-2-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 9.31 (s, 1H), 9.26 (s, 1H), 8.29 (d, J=9.1 Hz,1H), 7.62 (d, J=9.1 Hz, 1H), 7.54 (s, 1H), 4.55-4.44 (m, 1H), 4.38 (q,6.9 Hz, 2H), 3.98-3.89 (m, 1H), 3.88-3.80 (m, 1H), 1.57 (t, J=6.9 Hz,3H), 1.47 (d, J=6.8 Hz, 3H) ; MS (ESI) (M+H)⁺=356.5; HPLC analysis:99.0% purity.

Example 52 Compound 1641

1641:5-amino-3-(7-ethoxyquinolin-3-yl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 9.30 (s, 1H), 9.25 (s, 1H), 8.29 (d, J=8.9 Hz,1H), 7.61 (d, J=8.9 Hz, 1H), 7.52 (s, 1H), 4.37 (q, J=6.8 Hz, 2H), 4.06(s, 2H), 1.56 (t, J=6.8 Hz, 3H), 1.31 (s, 6H) ; MS (ESI) (M+H)⁺=370.6;HPLC analysis: 95.0% purity.

Example 53 Compound 1608

1608:5-amino-3-(7-ethoxyquinolin-3-yl)-1-(4-hydroxybutan-2-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, DMSO) δ 9.20 (d, J=1.8 Hz, 1H), 9.04 (s, 1H), 8.29 (d,J=9.1 Hz, 1H), 7.62 (s, 1H), 7.55 (dd, J=9.1, 1.8 Hz, 1H), 6.67 (s, 2H),4.56-4.50 (m, 1H), 4.29 (q, 6.9 Hz, 2H), 2.12-1.99 (m, 2H), 1.94-1.80(m, 2H), 1.45 (t, J=6.9 Hz, 3H), 1.38 (d, J=6.5 Hz, 3H) ; MS (ESI)(M+H)⁺=370.5; HPLC analysis: 97.3% purity.

Example 54 Compound 1596

1596:5-amino-3-(7-ethoxyquinolin-3-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, CDCl₃) 6 9.10 (s, 1H), 8.56 (d, J=9.7 Hz, 1H), 7.87 (s,1H), 7.71 (s, 1H), 7.36 (d, J=9.7 Hz, 1H), 6.04 (s, 2H), 5.36 (s, 2H),4.27 (q, J=6.9 Hz, 2H), 3.89 (s, 2H), 3.33 (s, 2H), 1.54 (t, J=6.9 Hz,3H), 1.07 (s, 6H) ; MS (ESI) (M+H)⁺=384.6; HPLC analysis: 98.7% purity.

Example 55 Compound 1597

1597:5-amino-1-(tert-butyl)-3-(2-ethoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, CDCl₃) δ 8.05 (d, J=8.4 Hz, 1H), 8.01 (d, J=8.8 Hz,1H), 7.94 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 5.42(s, 2H), 4.61 (q, J=6.9 Hz, 2H), 1.72 (s, 6H), 1.50 (t, J=6.9 Hz, 3H) ;MS (ESI) (M+H)⁺=354.7; HPLC analysis: 95.4% purity.

Example 56 Compound 1635

1635:5-amino-1-(cyclopropylmethyl)-3-(2-ethoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 8.67 (d, J=8.9 Hz, 1H), 8.26 (s, 1H), 8.05 (d,J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.9 Hz, 1H), 3.98 (d,J=6.8 Hz, 2H), 1.56 (t, J=6.9 Hz, 3H), 1.42-1.36 (m, 1H), 0.68-0.60 (m,2H), 0.54-0.44 (m, 2H) ; MS (ESI) (M+H)⁺=352.6; HPLC analysis: 95.0%purity.

Example 57 Compound 1633

1633:5-amino-1-cyclohexyl-3-(2-ethoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 8.88 (d, J=9.1 Hz, 1H), 8.38 (s, 1H), 8.15 (d,J=8.5 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.63 (d, J=9.1 Hz, 1H), 4.76 (q,J=7.0 Hz, 4H), 4.36-4.28 (m, 1H), 2.08-2.01 (m, 2H), 2.01-1.94 (m, 2H),1.93-1.85 (m, 2H), 1.83-1.74 (m, 2H), 1.55 (q, J=7.0 Hz, 3H), 1.39-1.24(m, 2H) ; MS (ESI) (M+H)⁻=380.6; HPLC analysis: 97.1% purity.

Example 58 Compound 1632

1632:5-amino-1-cycloheptyl-3-(2-ethoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 8.31 (d, J=9.0 Hz, 1H), 8.04 (d, J=1.8 Hz, 1H),7.93 (d, J=8.6 Hz, 1H), 7.85 (dd, J=8.6, 1.8 Hz, 1H), 7.11 (d, J=9.0 Hz,1H), 4.58 (q, J=7.1 Hz, 2H), 4.41-4.26 (m, 1H), 2.17-1.96 (m, 6H),1.95-1.81 (m, 2H), 1.81-1.71 (m, 2H), 1.69-1.59 (m, 4H), 1.49 (t, J=7.1Hz, 3H) ; MS (ESI) (M+H)⁺=394.6; HPLC analysis: 96.2% purity.

Example 59 Compound 1622

1622:5-amino-3-(2-ethoxyquinolin-6-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J=8.8 Hz, 1H), 7.95-7.88 (m, 2H),7.78 (d, J=8.5 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.29-5.67 (br, 2H), 5.31(s, 2H), 4.57 (q, J=7.0 Hz, 2H), 3.86 (s, 2H), 3.33 (s, 2H), 1.48 (t,J=7.0 Hz, 3H), 1.04 (s, 6H); MS (ESI) (M+H)⁺=384.6; HPLC analysis: 96.3%purity.

Example 60 Compound 1545

1545:5-amino-1-tert-butyl-3-(7-fluoroquinolin-3-yl)-1H-pyrazole-4-carboxamideExample 61 Compound 1554

1554:5-amino-1-tert-butyl-3-(7-chloroquinolin-3-yl)-1H-pyrazole-4-carboxamide.¹H NMR (300 MHz, CDCl₃) δ 9.29 (s, 1H), 8.65 (s, 1H), 8.32 (s, 1H), 7.94(d, J=8.3 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 5.77 (s, 2H), 1.69 (s, 9H) ;MS (ESI) (M+H)⁺=344.6; HPLC analysis: 97.4% purity.

Example 62 Compound 1555

1555:5-amino-1-tert-butyl-3-(7-(trifluoromethyl)quinolin-3-yl)-1H-pyrazole-4-carboxamide.¹H NMR (300 MHz, CDCl₃) δ 9.32 (s, 1H), 8.57 (s, 1H), 8.54 (s, 1H), 8.07(d, J=8.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 5.72 (s, 2H), 1.71 (s, 9H) ;MS (ESI) (M+H)⁺=378.5; HPLC analysis: 95.0% purity.

Example 63 Compound 1544

1544:5-amino-1-tert-butyl-3-(7-methylquinolin-3-yl)-1H-pyrazole-4-carboxamideExample 64 Compound 1592

1592:5-amino-1-(tert-butyl)-3-(7-ethylquinolin-3-yl)-1H-pyrazole-4-carboxamide.¹H NMR (300 MHz, CDCl₃) δ 9.12 (s, 1H), 8.41 (s, 1H), 8.03 (s, 1H), 7.83(d, J=8.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 5.72 (s, 2H), 5.16 (s, 2H),2.92 (q, J=7.5 Hz, 2H), 1.72 (s, 9H), 1.39 (t, J=7.5 Hz, 3H) ; MS (ESI)(M+H)⁺=338.5; HPLC analysis: 95.0% purity.

Example 65 Compound 1543

1543:5-amino-1-tert-butyl-3-(7-methoxyquinolin-3-yl)-1H-pyrazole-4-carboxamideExample 66 Compound 1565

1565:5-amino-1-tert-butyl-3-(7-(trifluoromethoxy)quinolin-3-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, CDCl₃) δ 9.23 (s, 1H), 8.51 (s, 1H), 8.09 (s, 1H), 7.97(d, J=8.9 Hz, 1H), 7.52 (d, J=8.9 Hz, 1H), 5.71 (s, 2H), 5.18 (s, 2H),1.72 (s, 9H); MS (ESI) (M+H)⁺=394.3; HPLC analysis: 97.2% purity.

Example 67 Compound 1569

1569:5-amino-1-(tert-butyl)-3-(7-isopropoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, CDCl₃) δ 9.04 (s, 1H), 8.29 (s, 1H), 7.77 (d, J=8.9 Hz,1H), 7.48 (s, 1H), 7.24 (d, J=8.9 Hz, 1H), 5.73 (s, 2H), 5.17 (s, 2H),4.87-4.74 (m, 1H), 1.73 (s, 9H), 1.47 (d, J=6.0 Hz, 6H) ; MS (ESI)(M+H)⁺=368.6; HPLC analysis: 98.0% purity.

Example 68 Compound 1566

1566:5-amino-1-tert-butyl-3-(7-propoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide.¹H NMR (300 MHz, CDCl₃) δ 9.24 (s, 1H), 8.84 (s, 1H), 7.98 (d, J=9.0Hz,1H), 7.82 (s, 1H), 7.48 (d, J=9.0 Hz, 1H), 5.89 (s, 1H), 4.20 (t, J=6.2Hz, 2H), 2.02-1.86 (m, 2H), 1.70 (s, 6H), 1.12 (t, J=7.4 Hz, 3H) ; MS(ESI) (M+H)⁺=368.5; HPLC analysis: 95.7% purity.

Example 69 Compound 1585

1585:5-amino-1-(tert-butyl)-3-(7-(cyclopropylmethoxy)quinolin-3-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, CDCl₃) δ 9.05 (s, 1H), 8.31 (s, 1H), 7.79 (s, 1H), 7.46(s, 1H), 7.31 (d, J=8.9 Hz, 1H), 5.72 (s, 2H), 5.17 (s, 2H), 4.01 (d,J=6.8 Hz, 2H), 1.72 (s, 9H), 1.45-1.35 (m, 1H), 0.84-0.64 (m, 2H),0.56-0.38 (m, 2H) ; MS (ESI) (M+H)⁺=380.4; HPLC analysis: 99.0% purity.

Example 70 Compound 1586

1586:5-amino-1-(tert-butyl)-3-(7-cyclopropoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 9.29 (s, 1H), 9.25 (s, 1H), 8.30 (d, J=9.0 Hz,1H), 7.86 (s, 1H), 7.63 (d, J=9.0 Hz, 1H), 4.20-4.11 (m, 1H), 1.71 (s,9H), 1.08-0.98 (m, 2H), 0.95-0.86 (m, 2H) ; MS (ESI) (M+H)⁺=366.5; HPLCanalysis: 99.8% purity.

Example 71 Compound 1643

1643:5-amino-1-(tert-butyl)-3-(2-cyclopropoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 8.24 (d, J=8.9 Hz, 1H), 8.00 (s, 1H), 7.96 (d,J=8.6 Hz, 1H), 7.82 (dd, J=8.6, 1.7 Hz, 1H), 7.06 (d, J=8.9 Hz, 1H),4.48 (td, J=6.2, 3.1 Hz, 1H), 1.69 (s, 9H), 0.93-0.87 (m, 2H), 0.86-0.79(m, 2H) ; MS (ESI) (M+H)⁺=366.4; HPLC analysis: 96.4% purity.

Example 72 Compound 1630

1630:5-amino-1-(tert-butyl)-3-(7-cyclobutoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 9.27 (s, 1H), 9.22 (s, 1H), 8.29 (d, J=9.1 Hz,1H), 7.58 (dd, J=9.1, 1.9 Hz, 1H), 7.41 (s, 1H), 5.08-4.99 (m, 1H),2.73-2.59 (m, 1H), 2.38-2.25 (m, 2H), 2.06-1.95 (m, 1H), 1.94-1.82 (m,1H), 1.71 (s, 9H); MS (ESI) (M+H)⁺=380.6; HPLC analysis: 99.0% purity.

Example 73 Compound 1639

1639:5-amino-1-(tert-butyl)-3-(2-cyclobutoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 8.89 (d, J=9.1 Hz, 1H), 8.34 (s, 1H), 8.17 (d,J=8.2 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.52 (d, J=9.1 Hz, 1H), 5.55-5.35(m, 1H), 2.79-2.61 (m, 2H), 2.51-2.32 (m, 2H), 2.10-1.98 (m, 1H),1.94-1.81 (m, 1H), 1.71 (s, 9H) ; MS (ESI) (M+H)⁺=380.5; HPLC analysis:98.3% purity.

Example 74 Compound 1657

1657:5-amino-3-(7-cyclobutoxyquinolin-3-yl)-1-cyclobutyl-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 9.32 (s, 1H), 9.26 (s, 1H), 8.29 (d, J=9.1 Hz,1H), 7.58 (d, J=9.1 Hz, 1H), 7.43 (s, 1H), 5.08-5.00 (m, 1H), 2.75-2.60(m, 4H), 2.53-2.39 (m, 2H), 2.37-2.25 (m, 2H), 2.04-1.83 (m, 4H); MS(ESI) (M+H)⁺=378.6; HPLC analysis: 97.4% purity.

Example 75 Compound 1656

1656:5-amino-3-(2-cyclobutoxyquinolin-6-yl)-1-cyclobutyl-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, CDCl₃) δ 8.09 (d, J=8.7 Hz, 2H), 7.97 (s, 1H), 7.85 (d,J=8.6 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 5.60-5.48 (m, 1H), 5.20 (s, 2H),4.63-4.51 (m, 1H), 2.86-2.73 (m, 2H), 2.68-2.56 (m, 2H), 2.52-2.40 (m,2H), 2.33-2.19 (m, 2H), 2.00-1.86 (m, 4H) ; MS (ESI) (M+H)⁺=378.7; HPLCanalysis: 97.8% purity.

Example 76 Compound 1658

1658:5-amino-3-(7-cyclobutoxyquinolin-3-yl)-1-cyclopentyl-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 9.28 (s, 1H), 9.23 (s, 1H), 8.28 (d, J=9.0 Hz,1H), 7.57 (d, J=9.0 Hz, 1H), 7.40 (s, 1H), 5.06-4.99 (m, 1H), 4.73-4.67(m, 1H), 2.70-2.58 (m, 2H), 2.37-2.24 (m, 2H), 2.20-2.04 (m, 4H),2.04-1.82 (m, 4H), 1.81-1.68 (m, 2H) ; MS (ESI) (M+H)⁺=392.6; HPLCanalysis: 98.7% purity.

Example 77 Compound 1653

1653:5-amino-3-(2-cyclobutoxyquinolin-6-yl)-1-cyclopentyl-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 8.88 (d, J=8.7 Hz, 1H), 8.34 (s, 1H), 8.16 (d,J=8.1 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 5.49-5.40(m, 1H), 4.75-4.67 (m, 2H), 2.77-2.60 (m, 2H), 2.49-2.33 (m, 2H),2.25-2.10 (m, 2H), 2.06-1.83 (m, 6H), 1.81-1.66 (s, 2H); MS (ESI)(M+H)⁺=392.5; HPLC analysis: 99.5% purity.

Example 78 Compound 1647

1647:5-amino-3-(7-cyclobutoxyquinolin-3-yl)-1-cyclohexyl-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 9.28 (s, 1H), 9.23 (s, 1H), 8.28 (d, J=9.0 Hz,1H), 7.57 (d, J=9.0 Hz, 1H), 7.42 (s, 1H), 5.07-5.00 (m, 1H), 4.25-4.11(m, 1H), 2.71-2.61 (m, 2H), 2.38-2.25 (m, 2H), 2.05-1.84 (m, 8H),1.83-1.73 (m, 1H), 1.61-1.47 (m, 2H), 1.38-1.24 (m, 1H); MS (ESI)(M+H)⁺=406.6; HPLC analysis: 97.2% purity.

Example 79 Compound 1646

1646:5-amino-3-(2-cyclobutoxyquinolin-6-yl)-1-cyclohexyl-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 8.88 (d, J=8.9 Hz, 1H), 8.37 (s, 1H), 8.15 (d,J=8.6 Hz, 1H), 8.01 (d, J=8.6 Hz, 2H), 7.52 (d, J=8.9 Hz, 1H), 5.52-5.41(m, 1H), 4.38-4.23 (m, 1H), 2.78-2.63 (m, 2H), 2.51-2.34 (m, 2H),2.08-2.00 (m, 2H), 2.00-1.93 (m, 2H), 1.92-1.83 (m, 4H), 1.82-1.74 (m,1H), 1.64-1.48 (m, 2H), 1.40-1.25 (m, 1H) ; MS (ESI) (M+H)⁺=406.6; HPLCanalysis: 96.3% purity.

Example 80 Compound 1644

1644:5-amino-3-(7-cyclobutoxyquinolin-3-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 9.28 (s, 1H), 9.23 (s, 1H), 8.29 (d, J=9.0 Hz,1H), 7.58 (d, J=9.0 Hz, 1H), 7.46 (s, 1H), 5.08-5.00 (m, 2H), 3.95 (s,2H), 2.74-2.61 (m, 2H), 2.39-2.24 (m, 2H), 2.06-1.95 (m, 1H), 1.95-1.82(m, 1H), 1.04 (s, 6H); MS (ESI) (M+H)⁺=410.6; HPLC analysis: 95.7%purity.

Example 81 Compound 1645

1645:5-amino-3-(2-cyclobutoxyquinolin-6-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide.¹H NMR (500 MHz, MeOD) δ 8.76 (d, J=8.6 Hz, 1H), 8.29 (s, 1H), 8.09 (d,J=7.2 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 5.50-5.40(m, 1H), 3.94 (s, 2H), 3.37 (s, 2H), 2.77-2.62 (m, 2H), 2.48-2.30 (m,2H), 2.09-1.95 (m, 1H), 1.95-1.77 (m, 1H), 1.04 (s, 6H); MS (ESI)(M+H)⁺=410.5; HPLC analysis: 99.7% purity.

Examples 82-103

Additional compounds were prepared using the above-disclosed methods:

Ex. Comp. Chemical Name and Chemical No. No. Structure Data 82 1570

5-amino-1-(tert-butyl)-3-(7-(2- methoxyethoxy)quinolin-3-yl)-1H-pyrazole-4-carboxamide MS (ESI) (M + H)⁺ = 384.5 83 1577

5-amino-3-(7-ethoxyquinolin-3- yl)-1-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide MS (ESI) (M + H)⁺ = 342.4 84 1587

5-amino-1-(tert-butyl)-3-(7- (neopentyloxy)quinolin-3-yl)-1H-pyrazole-4-carboxamide MS (ESI) (M + H)⁺ = 396.6 85 1588

5-amino-1-(tert-butyl)-3-(7- isobutoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide ¹H NMR (500 MHz, MeOD) δ 9.27 (s, 1H), 9.23 (s,1H), 8.30 (d, J = 9.2 Hz, 1H), 7.63 (dd, J = 9.2, 1.8 Hz, 1H), 7.55 (s,1H), 4.09 (d, J = 6.4 Hz, 2H), 2.35-2.16 (m, 1H), 1.72 (s, 9H), 1.15 (d,J = 6.6 Hz, 6H); MS (ESI) (M + H)⁺ = 382.4; HPLC analysis: 99.2% purity.86 1593

5-amino-3-(7-ethoxyquinolin-3- yl)-1H-pyrazole-4-carboxamide ¹H NMR (300MHz, MeOD) δ 8.94 (s, 1H), 8.46 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 9.0Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 9.0, 2.0 Hz, 1H), 4.25(q, J = 7.0 Hz, 2H), 1.51 (t, J = 7.0 Hz, 3H); MS (ESI) (M + H)⁺ =298.5; HPLC analysis: 99.0% purity. 87 1594

5-amino-3-(7-ethoxyquinolin-3- yl)-1-(2-methoxyethyl)-1H-pyrazole-4-carboxamide MS (ESI) (M + H)⁺ = 356.7 88 1595

5-amino-3-(7-ethoxyquinolin-3- yl)-N,1-bis(2-methoxyethyl)-1H-pyrazole-4-carboxamide MS (ESI) (M + H)⁺ = 414.8 89 1607

5-amino-1-(2,4-dimethylpentan-3- yl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide MS (ESI) (M + H)⁺ = 396.6 90 1609

6-(7-ethoxyquinolin-3-yl)-2-oxo- 2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxamide ¹H NMR (500 MHz, DMSO) δ 9.26 (d, J = 12.9 Hz,1H), 9.17 (s, 1H), 8.35 (d, J = 9.1 Hz, 1H), 7.72 (s, 1H), 7.59 (d, J =9.1 Hz, 1H), 6.77 (s, 2H), 4.88 (s, 2H), 4.30 (q, J = 6.7 Hz, 2H), 1.46(t, J = 6.7 Hz, 3H). MS (ESI) (M + H)⁺ = 338.5 91 1611

5-amino-3-(7-ethoxyquinolin-3- yl)-1-(3-hydroxybutan-2-yl)-1H-pyrazole-4-carboxamide ¹H NMR (500 MHz, MeOD) δ 8.99 (d, J = 12.0 Hz,1H), 8.55 (d, J = 7.6 Hz, 1H), 7.96 (d, J= 9.0 Hz, 1H), 7.42 (d, J = 1.8Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 4.26 (q, J = 7.0 Hz, 2H), 4.23-4.17(m, 1H), 4.16-4.05 (m, 1H), 1.60- 1.45 (m, 6H), 1.28 (d, J = 6.3 Hz,2H), 1.12 (d, J = 6.2 Hz, 2H). MS (ESI) (M + H)⁺ = 370.6 92 1612

5-amino-3-(7-ethoxyquinolin-3- yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide MS (ESI) (M + H)⁺ = 368.7 93 1626

5-amino-3-(7-ethoxyquinolin-3- yl)-1-(3-hydroxy-3-methylbutan-2-yl)-1H-pyrazole-4-carboxamide ¹H NMR (500 MHz, MeOD) δ 9.31 (s, 1H),9.26 (s, 1H), 8.30 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.54(s, 1H), 4.38 (q, J = 7.0 Hz, 2H), 4.36-4.29 (m, 1H), 1.59-1.53 (m, 6H),1.30 (s, 3H), 1.26 (s, 3H). MS (ESI) (M + H)⁺ = 384.6 94 1628

5-amino-3-(7-ethoxyquinolin-3- yl)-1-(3-methylbutan-2-yl)-1H-pyrazole-4-carboxamide MS (ESI) (M + H)⁺ = 368.6 95 1629

5-amino-1-(1,3-dihydroxypropan- 2-yl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide MS (ESI) (M + H)⁺ = 372.5 96 1631

5-amino-1-(1-cyclopropylethyl)-3- (7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide MS (ESI) (M + H)⁺ = 366.7 97 1634

5-amino-3-(2-ethoxyquinolin-6- yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide MS (ESI) (M + H)⁺ = 368.5 98 1636

5-amino-3-(2-ethoxyquinolin-6- yl)-1-(3-hydroxy-3-methylbutan-2-yl)-1H-pyrazole-4-carboxamide MS (ESI) (M + H)⁺ = 384.8 99 1637

5-amino-3-(7-ethoxyquinolin-3- yl)-1-(4-hydroxy-3,3-dimethylbutan-2-yl)-1H-pyrazole- 4-carboxamide ¹H NMR (500 MHz, MeOD) δ9.27 (s, 1H), 9.24 (s, 1H), 8.30 (d, J = 9.1 Hz, 1H), 7.62 (d, J = 9.1Hz, 1H), 7.51 (s, 1H), 4.48-4.35 (m, 5H), 1.61-1.50 (m, 6H), 1.11 (s,3H), 1.00 (s, 3H); MS (ESI) (M + H)⁺ = 398.6 100 1640

5-amino-3-(7-ethoxyquinolin-3- yl)-1-(1-methylcyclohexyl)-1H-pyrazole-4-carboxamide MS (ESI) (M + H)⁺ = 394.7 101 1654

5-amino-1-(tert-butyl)-3-(6- ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide MS (ESI) (M + H)⁺ = 354.6 102 1655

5-amino-1-cyclohexyl-3-(6- ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide ¹H NMR (500 MHz, MeOD) δ 8.85 (s, 1H), 8.31 (s,1H), 7.99 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 7.13 (s, 1H),4.15 (q, J = 6.9 Hz, 3H), 4.09 (s, 3H), 3.97- 3.79 (m, 1H), 1.93-1.83(m, 6H), 1.48 (t, J = 6.9 Hz, 3H), 1.44-1.35 (m, 2H), 1.32-1.18 (m, 2H).MS (ESI) (M + H)⁺ = 380.5 103 1661

5-amino-3-(2-ethoxyquinolin-6- yl)-1-isopropyl-1H-pyrazole-4-carboxamide ¹H NMR (500 MHz, MeOD) δ 8.86 (d, J = 8.9 Hz, 1H), 8.37 (s,1H), 8.15 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.61 (d, J =8.9 Hz, 1H), 4.76 (q, J = 6.6 Hz, 2H), 4.71-4.62 (m, 1H), 1.61 (t, J =6.6 Hz, 3H), 1.53 (d, J = 6.5 Hz, 6H). MS (ESI) (M + H)⁺ = 340.5; HPLCanalysis: 99.3% purity.

Example 104 Inhibition of TgCDPK1 and CpCDPK1

Inhibition of TgCDPK1 and CpCDPK1 was determined using a luminescentkinase assay which measures ATP depletion in the presence of the Syntide2 peptide substrate (KinaseGlo). For description of the methods andassays, see WO 2011/094628, incorporated by reference herein. Similar toTgCDPK1, exogenous calcium was necessary for CpCDPK1 to possess maximumcatalytic activity (data not shown). Notably, both kinases were testedat the same ATP concentration which allows direct comparison ofinhibitor potencies due to these enzymes possessing similar K_(m)s forthis cofactor. The following compounds were tested for inhibition ofTgCDPK1 and CpCDPK1 according to the known methods:

TABLE 1 TgCDPK1 and CpCDPK1 IC₅₀ data Entry Comp. TgCDPK1 CpCDPK1 No.No. IC₅₀ (μM) IC₅₀ (μM) 1 1 0.002 0.004 2 2 0.008 0.016 3 3 0.004 0.0044 4 0.033 0.043 5 5 0.13 0.13 6 6 0.035 0.064 7 7 0.003 0.001 8 8 0.0110.009 9 9 0.003 0.001 10 10 0.035 0.014 11 11 0.081 0.048 12 12 0.0080.011 13 13 0.006 0.007 14 14 0.008 0.016 15 15 0.007 0.010 16 16 0.0590.15 17 17 0.011 0.016 18 18 0.004 0.007 19 19 0.011 0.024 20 20 0.0260.013 21 21 0.039 0.017 22 22 0.015 0.021 23 23 0.005 0.018 24 24 0.0070.017 25 25 0.002 0.002 26 26 0.007 0.010 27 27 0.71 2.3 28 28 0.0400.42 29 29 0.017 0.20 30 30 0.032 0.15 31 31 0.64 >3 32 32 >3 >3 33 330.73 0.99 34 34 0.032 0.20 35 35 0.049 0.29 36 36 0.35 0.39 37 37 0.0100.070 38 38 0.006 0.007 39 39 0.002 0.001 40 1517 0.002 0.001 41 15720.008 0.005 42 1573 0.028 0.008 43 1591 0.021 0.007 44 1575 0.013 0.00545 1598 0.012 0.005 46 1652 0.012 0.003 47 1605 0.011 0.004 48 15710.008 0.005 49 1606 0.031 0.008 50 1604 0.006 0.002 51 1574 0.080 0.03052 1627 0.020 0.009 53 1641 0.041 0.021 54 1608 0.017 0.005 55 15960.011 0.005 56 1597 0.006 0.003 57 1635 0.006 0.003 58 1633 0.004 0.00259 1632 0.007 0.006 60 1622 0.007 0.002 61 1545 0.006 0.006 62 15540.036 0.022 63 1555 0.247 0.222 64 1544 0.016 0.011 65 1592 0.115 0.08566 1543 0.005 0.003 67 1565 0.031 0.038 68 1569 0.011 0.005 69 15660.005 0.003 70 1585 0.016 0.009 71 1588 0.086 0.052 72 1586 0.010 0.00573 1643 0.0057 0.003 74 1630 0.003 0.004 75 1639 0.005 0.006 76 16570.012 0.005 77 1656 0.007 0.003 78 1658 0.012 0.004 79 1653 0.012 0.00680 1647 0.019 0.008 81 1646 0.016 0.013 82 1644 0.012 0.005 83 16450.010 0.005 84 1570 0.258 0.255 85 1577 0.181 0.089 86 1587 0.175 0.49087 1593 0.164 0.067 88 1594 0.321 0.172 89 1595 0.723 0.398 90 16070.099 0.020 91 1609 1.433 0.577 92 1611 0.019 0.006 93 1612 0.010 0.00394 1626 0.03 0.013 95 1628 0.011 0.005 96 1629 0.12 0.052 97 1631 0.0100.005 98 1634 0.006 0.003 99 1636 0.058 0.018 100 1637 0.012 0.004 1011640 0.009 0.006 102 1654 >2 >2 103 1655 >2 >2 104 1661 0.005 0.002

Example 105 Additional Biological Data

A select group of compounds with low nanomolar IC₅₀s for CDPK1s weretested for inhibition of a mammalian kinase with a small gatekeeperresidue (Src), for inhibition of T. gondii cell proliferation, and forcytotoxicity against a mammalian cell line (CRL8155) using reportedprocedures (see WO 2011/094628, incorporated by reference herein). Theresults are summarized in Tables 2 and 3. Some of the compounds wereseveral thousand-fold selective for TgCDPK1 over Src. Most inhibitedparasite proliferation at sub-micromolar concentrations, and all of themdemonstrated low toxicity to mammalian cells.

TABLE 2 Further characterization of select compounds of the disclosure.Selectivity Cytotoxicity Entry Comp. Src IC₅₀ Index (Src/ T. gondii(CRL8155) No. No. (μM) TgCDPK1) EC₅₀ (μM) EC₅₀ (μM) 1 1 1.3 650 0.26 >402 3 7.3 1825 0.39 >30 3 18 0.98 245 0.26 >30 4 19 2.7 225 0.32 >40 5 256.9 >3500 0.072 >40 6 38 >10 >1600 1.1 >40 7 39 >30 >15000 0.22 >30

TABLE 3 Further characterization of select compounds of the disclosurewith solubility data. Cytotoxicity Entry Comp. T. gondii (CRL8155) SrcIC₅₀ Solubility No. No. EC₅₀ (μM) EC₅₀ (μM) (μM) pH = 6.5 1 15170.22 >30 >30 26 2 1597 0.20 >40 >10 83.5 3 1572 0.72 — >30 99.0 4 15981.21 >40 >10 26.5 5 1635 0.48 >40 >10 10.9 6 1652 0.52 >40 >10 10.9 71605 0.97 >40 >10 98.7 8 1571 0.33 — >10 34.3 9 1633 0.43 >40 >10 88.910 1604 0.41 >40 >10 8.5 11 1632 0.32 — — 46.5 12 1596 1.19 >40 >10 >10013 1622 0.21 >40 >10 >100 14 1545 2.25 >40 >30 >100 15 15430.59 >40 >30 >100 16 1569 1.21 >40 — >100 17 1566 0.69 >40 >10 12.7 181585 1.47 — — 26.8 19 1586 0.43 — 4.75 83.7 20 1643 0.045 >40 >10 96.321 1630 0.48 >40 >10 3.7 22 1639 0.48 >40 >10 80.6 23 1657 0.69 >40 >1076.1 24 1656 0.069 >40 >10 8.7 25 1658 0.40 >40 >10 59.7 26 16530.21 >40 >10 43.1 27 1647 1.14 >40 >10 87.8 28 1646 0.31 >40 >10 31.0 291644 0.77 >40 >10 97.5 30 1645 0.48 >40 >10 45.8

All compounds were assayed for inhibition of TgCDPK1 and CpCDPK1 and onthe small-gatekeeper (Thr) human kinases, Src and Abl. Human celltoxicity was evaluated in two human cell lines, HepG2 (hepatocellularcarcinoma) and CRL8155 (lymphoblast, spleen). hERG inhibition has beenassociated with long Q-T syndrome (cardiotoxicity), and the compoundswere evaluated for hERG inhibitory activity. The results comparingseveral compounds of the disclosure are shown in Table 4.

TABLE 4 Inhibit Parasite Cell toxicity hERG Comp. Enzyme Inhibition(IC₅₀, μM) Prolif. (EC₅₀, μM) (EC₅₀, μM) (IC₅₀, Solubility No. Tg CDPK1Cp CDPK1 SrcKD AbIKD T. gondii C. parvum HepG2 CRL 8155 μM) pH 6.5 15170.002 0.001 >10 >10 0.26 0.05 >40 >40 >30 26 1543 0.005 0.003 >10 >100.59 ND >40 >40 ND >100 1458 0.002 0.002 7 4.6 0.07 0.1 >40 >40 >10 181473 0.004 0.004 7.3 5.1 0.47 0.05 >40 >30 >10 15 1474 0.007 0.017.8 >10 0.37 ND >40 38 ND 10 1566 0.005 ND >10 >10 0.69 ND >40 16 ND 131571 0.007 ND 10 >10 0.62 ND >40 >40 ND 17 1572 0.006 ND >10 >10 0.23ND >40 >40 ND 99 ND = not done

Pharmacokinetic (PK) studies in mice for several compounds of thedisclosure are shown in Table 5. Maximum concentration (C_(max)), timeat which is observed (T_(max)) and area under the curve (AUC) areevaluated for the dosage of 10 mg/kg.

TABLE 5 Pharmacokinetic studies in mice PK (10 mg/kg) Entry No. Comp. NoC_(max) (μM) T_(max) (min) AUC (μM-min) 1 1517 9.9 60 2449.6 2 1597 5.380 1693.6 3 1571 4.6 80 1608.1 4 1585 7.1 140 3713.2 5 1458 3.1 30 356.5

Example 106 Selectivity in a Panel of Kinases

The selectivity of compound 39 for CpCDPK1 was evaluated. In particular,the activity for CpCDPK1was compared to the activity for over 20representative kinases. The results are shown in Table 5.

TABLE 5 Selectivity of compound 39. Kinase IC₅₀, μM K_(i), μM pKi CDPK10.0003 0.0008 9.52 Prkcn 1.11 0.427 6.37 **Kdr 2.46 0.569 6.24**EGFR >10 1.67 5.78 CAMK 1D{circumflex over ( )} >10 2.48 5.61*MAP3K10 >10 3.06 5.51 CAMKK2{circumflex over ( )} >10 3.1 5.51 MEK1 >103.29 5.48 **BRAF >10 3.37 5.47 **Rock1 >10 3.59 5.44 **FLT1 >10 3.675.44 p38 alpha >10 3.92 5.41 **AUR1 >10 4.05 5.39 Ck1alpha1 >10 4.125.39 ACVR1 >10 4.32 5.36 *CAMK2A{circumflex over ( )} >10 4.32 5.36*JAK3 >10 4.79 5.32 **Akt1 >10 5.01 5.30 Zipk{circumflex over ( )} >105.41 5.27 *ALK >10 5.79 5.24 **Erk2 >10 6.6 5.18 **/*Denotes Kinases(**) or close relatives (*) whose inhibition causes cardiotoxicity{circumflex over ( )}Denotes human kinases that are most closely relatedto CDPK1.

Example 107 Crystal Structure of TgCDPK1-Compound Complex

A crystal structure of the TgCDPK1-35 complex at 2.0 Å was obtained.Superposition of the structures of TgCDPK1 in complex with 35 and with aPP analog 2 shows that the compound 35 core can preserve the projectionsof N1 and C3 substitutions as well as hydrogen bond interactions withTgCDPK1 seen for the PP core (FIG. 1). The amide group of the compoundcore is essentially on top of the aminopyrimidine moiety of the PP core.Further away, on the naphthyl/quinolinyl and t-butyl substitutions, thematching carbons are 0.5-0.6 Å apart. It is not clear if the deviationsare caused by the difference in the aromatic rings or by the overallelectronic configurations of the two inhibitors. The two series ofinhibitors have different tolerance of methyl piperidine substituents onthe N1 position (i.e., R²) since these substitutions project distallyinto the ribose binding pocket and the solvent.

Example 108 T. gondii Infection in Mice

1×10⁵ T. gondii Type 1 RH strain tachyzoites expressing YFP wereinoculated i.p. into 4-5 wk old female CF-1 mice (n=4). After 48 h,compound 39 or vehicle-alone (PEG 400) were administered via oral gavageat 8 AM and 5 PM for 5 d. On day 8, the mice were killed, and underwentperitoneal lavage. T. gondii were enumerated via fluorescent microscopyand plotted, per mouse. Results are shown in FIG. 2. A dose response inefficacy was seen in that the mean parasite burden was decreased by 69%in the 5/10 mg/kg [AM/PM] group and 93% in the 20/40 mg/kg group.

Example 109 C. parvum Infection in Mice

Mice (7 wk old) were infected with 10⁶ oocysts of C. parvum Iowa strainby oral gavage. Mean oocysts shed in 250 mg mouse stool are shown frommice treated with compound 39 (1517) (squares, N=7) or vehicle alone(diamonds, N=7) are shown for each time point. Compound 39-treated micewere oral gavaged with compound 39 at a dose of 20 mg/kg at 8 AM and 40mg/kg at 5 PM on days 5-14 after infection. Control mice were givenvehicle alone by oral gavage at 8 AM and 5 PM on days 5-14 afterinfection). The number of oocysts in treated and vehicle groups wasquantified by qRT-PCR and normalized to the number of oocysts using astandard curve. Differences between groups were compared at each timepoint and p values calculated by non-parametric analysis ofKruskal-Wallis and for each time point, except before treatment (Days 0and 3), the difference was significant (p ≦0.05). The results areillustrated in FIG. 3.

Additional Results: In addition to these positive therapeutic tests invivo, compound 39 (1517) has been found to have parameters consistentwith CNS penetration (necessary for T. gondii therapeutics). Theseincluded excellent diffusion across the MDCK-PGP monolayer that predictsCNS penetration (=563 nm/sec, similar to a positive control CNSpenetrant molecule) and 25% brain levels/plasma levels in orally-dosedmice at 1 hour after dosing. Finally, compound 39 (1517) has been testedby AbbVie in their panel of 80 human protein kinases (hPKs) and 24off-target liabilities (e.g. ion channels, G-protein receptors). No hPKswere inhibited at levels up to 3 μM and no signal was detected in the 24off-target liability screen. These results demonstrate that thecompounds of the disclosure can be specific for CDPKs.

In addition, compound 39 (1517) has shown good solubility, goodstability, and higher oral availability than the compound of prior art,3-(6-ethoxynaphthalen-2-yl)-1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound 9, also 1294). In addition, hERGinhibition has been associated with long Q-T syndrome (cardiotoxicity),and compounds without the recombinant hERG binding present betterclinical candidates. Indeed, compound 39 (1517) has shown no hERGinhibitory activity as compared to compound 9 (1294).

Example 110 Efficacy in Calf Model

The calf model is a clinical model of C. parvum, as calves developprofuse watery diarrhea commencing 2-3 days PI which peaks around day7-8. Diarrhea is less severe or sometimes resolved by day 10 PI. A totalof six male calves per treatment or control group are used, allowingpotential exclusion of up to one animal from each group withoutcompromising statistical analyses. All calves are sourced from the sameclosed herd of approximately 12,000 Holstein dairy cows at ShamrockDairy (Casa Grande, Ariz.). Beginning at 12 h of age, calves aremaintained on milk replacer twice daily until end of the experiment atday 10 post challenge. For efficacy evaluation against C. parvum, eachcalf is challenged by oral inoculation with 3×10⁷ oocysts on day 0, when36-48 h of age. At challenge and every 12 h thereafter until the end ofthe experiment, calves are orally administered an individual BKI.Dosages of 10 mg/kg/day and 100 mg/kg/day are evaluated, but the actualdosage and intervals may be modified based on expected PK fromallometric dose adjustments, the compound protein binding of calfplasma, and the relative metabolism of compounds by bovine livermicrosomes. Control calves are identically infected and treated withvehicle alone. Fecal samples are examined for oocysts prior to challengeand daily thereafter to determine pre-patent and patent periods. Totaldaily oocyst counts for each calf are determined by real-time PCR usingfeces collected over successive 24 h periods. Clinical andparasitological data is analyzed statistically by ANOVA using theGeneral Linear Modes Program. Fecal samples are collected at 80 h postchallenge for measurement of stool BKI content (control: pre-infectionstools). Plasma BKI levels are measured from calves at the first andlast peaks and troughs. Blood is collected at the end of BKI dosing forCBC and a complete metabolic profile to screen for toxicity. Calves areeuthanized on day 10 Pl. Tissues are evaluated for toxicologicpathology. Feces from each calf are examined for possible bacterial andviral enteropathogens by standard methods operative in the ArizonaVeterinary Diagnostic Laboratory.

Example 111 Efficacy in Sheep Model

Pregnant sheep are selected from a high health status closed pure Churrabreed flock. For each compound, enough number of sheep are oestrussynchronized and fertilized through programmed mating in the flockPregnancy diagnose are carried out through ultrasound scan (US) at 40days of gestation. Each group consists of two pregnant sheep. Rectaltemperatures are recorded 2 days before drug supplying and then dailyduring the experiment. Blood samples are taken weekly and analyzed tomonitor health status. Sheep are also monitored by ultrasound scan (US)weekly throughout the experiment until lambing or fetal death. When thisoccurs, sheep and lamb/fetus are euthanized and complete PM carried out.Blood is collected pre-dosing (control), and after the first and fifthdosage, 1, 2, 4, 8 and 24 hrs (48 hrs for every other dosing). Blood iscollected with EDTA and plasma separated. Three days after the end ofthe exposure, blood is worked up for a complete blood count and fullchemistry and the animals are sacrificed and liver, kidney, muscle, andplacenta are examined histologically for toxicity.

For testing each compound, pregnant sheep are randomly allocated indifferent groups: 1) treated and challenged with N. caninum; 2) treatedand challenged with T. gondii; 3) non-treated and challenged with N.caninum; 4) non-treated and challenged with T. gondii; 5) treated andnon-challenged; and 6) non-treated, non-challenged. Each group iscomposed of seven sheep. Treatments are supplied from day 5 to day 15after infection on animals from groups 1,2 and 5, following the scheduleestimated from the results obtained above in the PK studies to givevalues above the EC90 for the organism throughout the dosing interval.Animals in groups 3, 4 and 6 remain untreated. On day 90 of gestation,sheep to be infected with N. caninum (groups 1 and 3), is inoculatedintravenously (i.v.) with 2 ml PBS containing 10⁶ live N. caninumtachyzoites of the Nc-Spain7 isolate. Sheep to be infected with T.gondii (groups 2 and 4) are orally inoculated with 50 sporulated oocystsof the M4 isolate. The animals from group 4 do not receive any drugtreatment and will be administered orally with PBS (diluent of T. gondiioocysts) and the animals in group 2 are inoculated intravenously with acomparable number of cells from the same cell-line used as host cell forgrowth of N. caninum tachyzoites. Rectal temperatures are recorded 2days before inoculation and then daily until 14 days post infection(p.i.), later once a week. Blood samples are taken weekly and analyzedto monitor health status. Heparinised blood and serum are also taken tomonitor specific immune responses against the parasites. Lambs and damsare culled at day 7 after birth or immediately after detection of fetalmortality. Samples are collected for histopathological, PK analyses andPCR-parasite detection and quantification. A sample of thoracic liquidfrom aborted fetuses of precalostral serum from lambs is collected forserology. Antibody responses, cellular immune responses (IFN-y),histopathology, and DNA extraction of tissue samples/Neospora andToxoplasma PCRs are evaluated.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be incorporated within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated herein by referencefor all purposes.

1-55. (canceled)
 56. A method for treating an apicomplexan protozoanrelated disease comprising providing to a patient in need of suchtreatment a therapeutically effective amount of either a compound offormula:

or a pharmaceutically acceptable salt thereof or a pharmaceuticalcomposition thereof, wherein R¹ is one of the formulas:

wherein n is 0; each R⁷ is independently halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆ haloalkyl, —OR¹⁰, —SR¹⁰, —N(R¹⁰)₂, —C(O)R¹⁰), —C(O)OR¹⁰,—C(O)N(R¹⁰)₂, —S(O)₂R¹⁰, —OC(O)R¹⁰, —OC(O)OR¹⁰, —OC(O)N(R¹⁰)₂,—N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)C(O)OR¹⁰, or —N(R¹⁰)C(O)N(R¹⁰)₂, wherein each R¹⁰is independently hydrogen or C₁₋₆ alkyl; R⁸ is hydrogen, halogen, cyano,nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or —Q—R^(8′); Q is —O—, —S, —NH, orN(C₁₋₆ alkyl); R^(8′) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆ alkyl,heteroaryl, or heteroarylC₁₋₆ alkyl, wherein the alkyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl are optionally substituted with one,two, three, or four groups that are each independently halogen, cyano,nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR¹⁴, —SR¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴,—C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —S(O)₂R¹⁴, —OC(O)R¹⁴, —OC(O)OR¹⁴,—OC(O)N(R¹⁴)₂, —N(R¹⁴)C(O)R¹⁴, —N(R¹⁴)C(O)OR¹⁴, or —N(R¹⁴)C(O)N(R¹⁴)₂,wherein each R¹⁴ is independently hydrogen or C₁₋₆ alkyl; and each R⁹ isindependently hydrogen or C₁₋₆ alkyl; R² is hydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, —C₁₋₄ alkyl-R¹², C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,monocyclic heterocyclyl, monocyclic heteroaryl, or phenyl, wherein thealkyl, cycloalkyl, heterocyclyl, heteroaryl, and phenyl groups are eachoptionally substituted with one or two R¹³ groups; each R¹³ isindependently C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR, —SR, —NR₂, —C(O)R,—C(O)OR, —C(O)NR₂, —S(O)₂NR₂, or —S(O)₂R: and where R¹² is —OR, —SR,—NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —S(O)₂R, —OC(O)R, —OC(O)OR, —OC(O)NR₂,—N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR₂, phenyl, monocyclic heteroaryl,C₃₋₈ cycloalkyl, or monocyclic heterocyclyl, wherein the aryl,heteroaryl, C₃₋₈ cycloalkyl, and heterocyclyl groups are each optionallysubstituted by one, two, or three groups that are each independentlyhalogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR, —SR, —NR₂,—C(O)R, —C(O)OR, —C(O)NR₂, —S(O)₂R, —OC(O)R, —OC(O)OR, —OC(O)NR₂,—N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)NR₂; and each R is independentlyhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl,heterocyclyl, aryl, aryl C₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl are optionally substituted with one, two, three, or fourgroups that are each independently halogen, cyano, nitro, C₁₋₆ alkyl,C₁₋₆ haloalkyl, —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂,—S(O)₂R⁰, —OC(O)R⁰, —OC(O)OR⁰, —OC(O)N(R⁰)₂, —N(R⁰)C(O)R⁰,—N(R⁰)C(O)OR⁰, or —N(R⁰)C(O)N(R⁰)₂, wherein each R⁰ is independentlyhydrogen or C₁₋₆ alkyl; or R² and R³ together with the atoms to whichthey are attached form 2-oxo-2,3-dihydro-imidazolyl ring; R³ and R⁴ areindependently hydrogen; and R⁵ and R⁶ are independently hydrogen. 57.The method of claim 56, wherein the apicomplexan protozoan relateddisease is toxoplasmosis, cryptosporidiosis, malaria neosporosis,eimeriosis, or coccidiosis.
 58. A method according to claim 56, whereinR¹ is one of the formulas:


59. A method according to claim 58, wherein R¹ is of the formula:


60. A method according to claim 58, wherein R¹ is of the formula:


61. A method according to claim 58, wherein R⁸ is —Q—R^(8′); wherein Qis —O—, —S—, —NH—, or —N(C₁₋₆ alkyl)—; R⁸ is hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl wherein the alkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl are optionally substitutedwith one, two, three, or four groups that are each independentlyhalogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR¹⁴, —SR¹⁴,—N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂, —S(O)₂R¹⁴, —OC(O)OR¹⁴,—OC(O)OR¹⁴, —OC(O)N(R¹⁴)₂, —N(R¹⁴)C(O)R¹⁴, —N(R¹⁴)C(O)OR¹⁴, or—N(R¹⁴)C(O)N(R¹⁴)₂, wherein each R¹⁴ is independently hydrogen or C₁₋₆alkyl.
 62. A method according to claim 61, wherein R^(8′) is C₁₋₆ alkyloptionally substituted with one, two, three, or four groups that areeach independently halogen, —OR¹⁴, —SR¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴,—C(O)N(R¹⁴)₂, or —S(O)₂R¹⁴, wherein each R¹⁴ is independently hydrogenor C₁₋₆ alkyl.
 63. A method according to claim 62, wherein R⁸′ is C₁₋₆alkyl.
 64. A method according to claim 62, wherein R⁸′ is ethyl.
 65. Amethod according to claim 58, wherein R⁸ is hydrogen, halogen, C₁₋₆alkyl, or C₁₋₆ haloalkyl.
 66. A method according to claim 56, wherein R¹is one of the formulas:


67. A method according to claim 56, wherein each R⁷ is independentlyhalogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR¹⁰, —N(R¹⁰)₂,—C(O)R¹⁰, —C(O)OR¹⁰, or —C(O)N(R¹⁴)₂, wherein each R¹⁰ is independentlyhydrogen or C₁₋₆ alkyl.
 68. A method according to claim 56, wherein eachR⁷ is independently halogen, cyano, nitro, C₁₋₆ alkyl, or C₁₋₆haloalkyl.
 69. A method according to claim 56, wherein R¹ is one of theformulas:


70. A method according to claim 56, wherein each R⁹ is independentlyhydrogen or C₁₋₄ alkyl.
 71. A method according to claim 56, wherein R²is C₁₋₆ alkyl, C₁₋₆ haloalkyl, —C₁₋₄ alkyl-R¹², C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, monocyclic heterocyclyl, monocyclicheteroaryl, or phenyl, wherein the alkyl, cycloalkyl, heterocyclyl,heteroaryl, and phenyl groups are each optionally substituted with oneor two R¹³ groups.
 72. A method according to claim 71, where R¹² is —OR,—NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —S(O)₂R, phenyl, monocyclic heteroaryl,C₃₋₈ cycloalkyl, or monocyclic heterocyclyl, wherein the aryl,heteroaryl, C₃₋₈ cycloalkyl, and heterocyclyl groups are each optionallysubstituted by one, two, or three groups that are each independentlyhalogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR, —SR, —NR₂,—C(O)R, —C(O)OR, —C(O)NR₂, —S(O)₂R, —OC(O)R, —OC(O)OR, —OC(O)NR₂,—N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)NR₂.
 73. A method according toclaim 72, where R¹² is —OR.
 74. A method according to claim 56, whereinR² is C₃₋₈ cycloalkyl or monocyclic heterocyclyl, each optionallysubstituted with one or two R¹³ groups.
 75. A method according to claim56, wherein the compound is selected from:5-amino-1-tert-butyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-tert-butyl-3-(6-ethoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide;1-tert-butyl-3-(6-ethoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(naphthalen-2-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazole-4-carboxamide;5-amino-3-(6-ethoxynaphthalen-2-yl)-1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazole-4-carboxamide;5-amino-3-(6-methoxynaphthalen-2-yl)-1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazole-4-carboxamide;5-amino-3-(6-methoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-ethyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-isopropyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-isobutyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(cyclopropylmethyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(cyclohexylmethyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-cyclohexyl-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(naphthalen-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide;5-amino-3-(naphthalen-2-yl)-1-neopentyl -1H-pyrazole-4-carboxamide;5-amino-1-(1-methylpiperidin-4-yl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-((1-methylpiperidin-4-yl)methyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(2-hydroxyethyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(2-morpholinoethyl)-3-(naphthalen-2-yl)-1H-pyrazole-4-5-amino-1-(tert-butyl)-3-(6-hydroxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(6-methoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(6-propoxynaphthalen-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(2-methylbenzofuran-3-yl)-1H-pyrazole-4-carboxamide;3-(3-amino-1H-indazol-6-yl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide;3-(3-amino-1-methyl-1H-indazol-6-yl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(2-amino-1-methyl-1H-benzo[d]imidazol-5-yl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(2-oxo-2H-chromen-6-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(quinolin-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(6-ethoxyquinolin-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(quinolin-6-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(quinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-isopropyl-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-isobutyl-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-neopentyl-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide;5-amino-1-(cyclopropylmethyl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;1-isobutyl-3-(2-(2,2,2-trifluoroethoxy)quinolin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.5-amino-1-cyclopentyl-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-cyclohexyl-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide;5-amino-1-cycloheptyl-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(cyclohexylmethyl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-(1-hydroxypropan-2-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-(4-hydroxybutan-2-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(2-ethoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(cyclopropylmethyl)-3-(2-ethoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide;5-amino-1-cyclohexyl-3-(2-ethoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide;5-amino-1-cycloheptyl-3-(2-ethoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(2-ethoxyquinolin-6-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide;5-amino-1-tert-butyl-3-(7-fluoroquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-tert-butyl-3-(7-chloroquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-tert-butyl-3-(7-(trifluoromethyl)quinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-tert-butyl-3-(7-methylquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(7-ethylquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-tert-butyl-3-(7-methoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-tert-butyl-3-(7-(trifluoromethoxy)quinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(7-isopropoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-tert-butyl-3-(7-propoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(7-(cyclopropylmethoxy)quinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(7-cyclopropoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(2-cyclopropoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(7-cyclobutoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(2-cyclobutoxyquinolin-6-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-cyclobutoxyquinolin-3-yl)-1-cyclobutyl-1H-pyrazole-4-carboxamide;5-amino-3-(2-cyclobutoxyquinolin-6-yl)-1-cyclobutyl-1H-pyrazole-4-carboxamide;5-amino-3-(7-cyclobutoxyquinolin-3-yl)-1-cyclopentyl-1H-pyrazole-4-carboxamide;5-amino-3-(2-cyclobutoxyquinolin-6-yl)-1-cyclopentyl-1H-pyrazole-4-carboxamide;5-amino-3-(7-cyclobutoxyquinolin-3-yl)-1-cyclohexyl-1H-pyrazole-4-carboxamide;5-amino-3-(2-cyclobutoxyquinolin-6-yl)-1-cyclohexyl-1H-pyrazole-4-carboxamide;5-amino-3-(7-cyclobutoxyquinolin-3-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide;5-amino-3-(2-cyclobutoxyquinolin-6-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(7-(2-methoxyethoxy)quinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(7-(neopentyloxy)quinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(7-isobutoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-(2-methoxyethyl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-N,1-bis(2-methoxyethyl)-1H-pyrazole-4-carboxamide;5-amino-1-(2,4-dimethylpentan-3-yl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;6-(7-ethoxyquinolin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-(3-hydroxybutan-2-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-(3-hydroxy-3-methylbutan-2-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-(3-methylbutan-2-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(1,3-dihydroxypropan-2-yl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-(1-cyclopropylethyl)-3-(7-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(2-ethoxyquinolin-6-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(2-ethoxyquinolin-6-yl)-1-(3-hydroxy-3-methylbutan-2-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-(4-hydroxy-3,3-dimethylbutan-2-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(7-ethoxyquinolin-3-yl)-1-(1-methylcyclohexyl)-1H-pyrazole-4-carboxamide;5-amino-1-(tert-butyl)-3-(6-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-1-cyclohexyl-3-(6-ethoxyquinolin-3-yl)-1H-pyrazole-4-carboxamide;5-amino-3-(2-ethoxyquinolin-6-yl)-1-isopropyl-1H-pyrazole-4-carboxamide; and pharmaceutically acceptable saltthereof.